Nanoporous layers using thermal dealloying

ABSTRACT

The present invention relates generally to medical devices with therapy eluting components and methods for making same. More specifically, the invention relates to implantable medical devices having at least one porous layer, and methods for making such devices, and loading such devices with therapeutic agents. A mixture or alloy is placed on the surface of a medical device, then one component of the mixture or alloy is generally removed without generally removing the other components of the mixture or alloy. In some embodiments, a porous layer is adapted for bonding non-metallic coating, including drug eluting polymeric coatings. A porous layer may have a random pore structure or an oriented or directional grain porous structure. One embodiment of the invention relates to medical devices, including vascular stents, having at least one porous layer adapted to resist stenosis or cellular proliferation without requiring elution of therapeutic agents. The invention also includes methods, devices, and specifications for loading of drugs and other therapeutic agents into nanoporous coatings.

CROSS-REFERENCE TO RELATED APPLICATIONS

The present application is a continuation of U.S. application Ser. No.11/200,655 filed Aug. 10, 2005, which 1) claims priority under 35 U.S.C.§119(e) to U.S. Provisional Application No. 60/602,542 filed on Aug. 18,2004, U.S. Provisional Application No. 60/613,165 filed on Sep. 24,2004, U.S. Provisional Application No. 60/664,376 filed on Mar. 23,2005, and U.S. Provisional Application Serial No. 60/699,302 filed Jul.14, 2005, and 2) is a continuation-in-part of U.S. application Ser. No.10/918,853 filed on Aug. 13, 2004, which is a continuation-in-part ofU.S. application Ser. No. 10/713,244 filed on Nov. 13, 2003, whichclaims priority under 35 U.S.C. §119(e) to U.S. Provisional ApplicationNo. 60/426,106 filed on Nov. 13, 2002, the disclosures of which areincorporated by reference herein in their entirety.

BACKGROUND OF THE INVENTION

1. Field of the Invention

The present invention relates generally to medical devices with porouslayers and methods for making the same. More specifically, the inventionrelates to implantable medical devices having at least one porous layer,methods for making such devices and loading the porous layer withtherapeutic agents. The porous layer may be used as a bonding interfacefor other coatings applied to the medical device, including drug-elutingcoatings. The porous layer may have a random pore structure or anoriented or directional pore structure. The invention also relates toimplantable medical devices having at least one porous layer that do notrequire loading with a therapeutic agent.

2. Description of the Related Art

Implantable medical devices are increasingly being used to deliver oneor more therapeutic agents to a site within a body. Such agents mayprovide their own benefits to treatment and/or may enhance the efficacyof the implantable device. For example, much research has been conductedinto the use of drug eluting stents for use in percutaneous transluminalcoronary angioplasty (PTCA) procedures. Although some implantabledevices are simply coated with one or more therapeutic agents, otherdevices include means for containing, attaching or otherwise holdingtherapeutic agents to provide the agents at a treatment location over alonger duration, in a controlled release manner, or the like.

Porous materials, for example, are commonly used in medical implants asreservoirs for the retention of therapeutic agents. Materials that havebeen used for this purpose include ceramics such as hydroxyapatites andporous alumina, as well as sintered metal powders. Polymeric materialssuch as poly(ethylene glycol)/poly(L-lactic acid) (PLGA) have also beenused for this purpose.

SUMMARY OF THE INVENTION

It is desirable to modify medical devices, particularly coronary stents,in order to confer on these devices the ability to carry and elutetherapeutic agents. To date, materials such as hydroxyapatites, porousalumina, sintered metal powders and polymers have been used for thispurpose. Each has had its limitation. Polymer coatings, for example,have limitations related to coating adhesion, mechanical properties,inflammatory properties, and material biocompatibility, while porousalumina has severe issues with regard to mechanical integrity. Thepreferred embodiments of the invention related to nanoporous metallicsurface modification as an alternative means of enabling targeteddelivery of therapeutic agents from medical devices. The said surfacemodification results in one or more layers of porous metal on thesurface of the medical device. The porous layers are then loaded withthe therapeutic agent of choice, or a combination of such agents.

Some embodiments of the invention are geared toward producing a stronglyadherent and mechanically robust biocompatible porous layer(s), whilesimplifying device manufacture and loading of therapeutic agents. Theporous layer(s) are generated by the process of dealloying in which asacrificial material is selectively removed from a precursor alloy onthe medical device. The said precursor alloy may be formed by thin filmdeposition processes. The dealloying process can be effected bothchemically and thermally, both methods of which are described in thisinvention. The morphology of the porous layer, e.g. pore size, thicknessand tortuosity can be adjusted at point of manufacture to accommodatethe need for different elution profiles as may be required by themedical application at hand. Within the same medical application, e.g.the treatment of coronary restenosis, different morphologies may bedesired to accommodate different elution profiles for differenttherapeutic agents. The invention also comprises unique loading methodswhich, independently or in conjunction with the ability to varymorphology, allow one or more therapeutic agents to be loaded into theporous layers to achieve desired elution profiles. Some of the loadingmethods allow deposition of dilute or extremely dense crystalline formsof therapeutic agents within the porous structure thereby allowing awide range of control over initial payloads within a relatively thinlayer.

In addition, the porous layer(s) can be loaded with or bonded todrug-carrying polymers, such as those used currently with the Cypherstent, with the intent to improve the adhesion of said polymer(s) i.e.when the polymer flows into the porous layer(s), it solidifies to form arooting or anchoring system. Alternatively, the porous layer(s) can beloaded with one or more therapeutic agents, prior to the application ofa drug-free topcoat polymer to moderate elution kinetics. In oneembodiment, biodegradable polymers are applied as a topcoat and throughselection of polymer solvents with varying solubility properties for thetherapeutic agents, one can achieve controlled mixing of the therapeuticagent with the polymer, as well as control the extent of penetration ofthe polymer-drug mixture into the porous layer.

In one embodiment of the invention, a stent for insertion into a bodystructure is provided. The stent comprises a tubular member having afirst end and a second end, a lumen extending along a longitudinal axisbetween the first end and the second end, an outer or ablumenal surfaceand an inner or lumenal surface, and at least one porous layer where theporous layer comprises an interstitial structure and an interstitialspace. The interstitial space is generally configured by the removal ofat least one sacrificial material from a mixture comprising at least onesacrificial material with one or more structural materials that comprisethe interstitial structure of the porous layer. The porous layer may beadapted to receive and release at least one therapeutic agent. The stentmay also further comprise a therapeutic agent within at least a portionof the interstitial space. In one embodiment, the interstitial space isgenerally configured by a dealloying process. In one embodiment of theinvention, at least a portion of the porous layer extends between theouter surface and the lumenal surface.

In one embodiment, the porous layer is adapted to bond to a drug elutingcoating. The porous layer may have an average thickness of about 0.1microns to about 1000 microns, and preferably about 0.1 microns to about10 microns. The porous layer may have an average pore size of about 1nanometer to about 100 microns. In other embodiments, the average poresize is about 10 nanometers to about 100 microns. The porous layer mayhave an average porosity of about 1% to about 99%, typically about 25%to about 75%, and preferably about 50% to about 70%. Most preferably,the porous layer has an average porosity of about 40% to about 60%. Thestent may further comprise a non-metallic drug eluting coating bonded toat least a portion of the porous layer. The porous layer may be ametallic porous layer. The porous layer may be nanoporous. The drugeluting coating may be a polymeric or hydrogel drug eluting coating. Thedrug of the drug eluting coating may be selected from a group comprisingactinomycin-D, batimistat, c-myc antisense, dexamethasone, paclitaxel,taxanes, sirolimus, tacrolimus and everolimus, unfractionated heparin,low-molecular weight heparin, enoxaprin, bivalirudin, tyrosine kinaseinhibitors, Gleevec, wortmannin, PDGF inhibitors, AG1295, rho kinaseinhibitors, Y27632, calcium channel blockers, amlodipine, nifedipine,and ACE inhibitors, synthetic polysaccharides, ticlopinin, dipyridamole,clopidogrel, fondaparinux, streptokinase, urokinase, r-urokinase,r-prourokinase, rt-PA, APSAC, TNK-rt-PA, reteplase, alteplase,monteplase, lanoplase, pamiteplase, staphylokinase, abciximab,tirofiban, orbofiban, xemilofiban, sibrafiban, roxifiban, ABT-578,CCI-779, biolimus-A9, temsirolimus, anti-CD34 antibodies, mycophenolicacid, Vitamin E, omega-3 fatty acids, tempamine, and docetaxel, an agentfor altering cytochrome P450 function, cyclosporine, an azole antifungal agent, itraconazole, ketoconazole, a macrolide antibiotic,clarithromycin, erythromycin, troleandomycin, an non-nucleoside reversetranscriptase inhibitor, delavirdine, a protease inhibitor, indinavir,ritonavir, saquinavir, ritonavir, grapefruit juice extract,mifepristone, nefazodone, a rifamycin including rifabutin, rifampin andrifapentine, an anti-convulsant including carbamazepine, phenobarbitaland phenytoin, an anti-HIV agent including efavirenz and nevirapine, andan herbal agent including St. John's Wort, an anti-restenosis agent, ananti-thrombogenic agent, an antibiotic, an anti-platelet agent, ananti-clotting agent, an anti-inflammatory agent, an anti-neoplasticagent, a chelating agent, penicillamine, triethylene tetraminedihydrochloride, EDTA, DMSA (succimer), deferoxamine mesylate, aradiocontrast agent, a radio-isotope, a prodrug, antibody fragments,antibodies, live cells, therapeutic drug delivery microspheres ormicrobeads, gene therapy agents, viral vectors and plasmid DNA vectors.

In one embodiment, the average pore size of the porous layer is withinthe range of about 1 nanometers to about 1,000 nanometers. In otherembodiments, the average pore size of the porous layer is within therange of about 1 nanometers to about 100 nanometers and preferablywithin the range of about 1 nanometers to about 20 nanometers. In oneembodiment of the invention, the structural material comprises gold andthe average pore size of the porous layer is within the range of about 5nanometers to about 500 nanometers.

The average thickness of porous layer in one embodiment is within therange of about 2 nanometers to about 5 mm. In another embodiment, theaverage thickness is within the range of about 5 nanometers to about 5micrometers and preferably within the range of about 5 nanometers toabout 50 nanometers. In still another embodiment, the average thicknessof the porous layer is about 10 nanometers. In another embodiment of theinvention, the average thickness is in the range of about 0.5 μm to 5μm, and preferably about 0.1 μm. In another embodiment of the invention,the average thickness is in the range of about 0.5 um to 5 um, andpreferably about 1 um to about 2 um.

In one embodiment, the interstitial volume per volume of porous layer isbetween about 10% and about 90%. The porous layer may have asubstantially nonuniform interstitial volume per volume of porous layer.In some embodiments, the nonuniformity of the interstitial volume pervolume of porous layer is graded. In other embodiments, thenonuniformity of the interstitial volume per volume of porous layer isabrupt. In one embodiment, the stent comprises a first zone having afirst average interstitial volume per volume of porous layer and asecond zone having a second average interstitial volume per volume ofporous layer.

In some embodiments, the porous layer has a nonuniform pore size. Thestent may comprise a first zone having a first average pore size and asecond zone having a second average pore size. The pore size maytransition gradually between the first zone and the second zone.

The porous layer may also have a nonuniform layer thickness. The stentmay comprise a first thickness at a first point and a second thicknessat a second point. The layer of thickness may transition graduallybetween the first point and the second point. In one embodiment, theporous layer has a substantially nonuniform pore size along thelongitudinal axis of the tubular member. In one embodiment, the porouslayer has a substantially nonuniform pore size circumferentially aroundthe tubular member. In one embodiment, the porous layer has a nonuniformlayer thickness along the longitudinal axis of the tubular member and inone embodiment, the porous layer has a nonuniform layer thickness aroundthe circumference of the tubular member. The interstitial volume pervolume of porous layer may also be nonuniform along the longitudinalaxis of the tubular member and also nonuniform around the circumferenceof the tubular member.

In another embodiment, the stent further comprises at least onetherapeutic agent that is at least partially contained within theinterstitial space of the porous layer. The therapeutic agent isselected from the group comprising actinomycin-D, batimistat, c-mycantisense, dexamethasone, paclitaxel, taxanes, sirolimus, tacrolimus andeverolimus, unfractionated heparin, low-molecular weight heparin,enoxaprin, bivalirudin, tyrosine kinase inhibitors, Gleevec, wortmannin,PDGF inhibitors, AG1295, rho kinase inhibitors, Y27632, calcium channelblockers, amlodipine, nifedipine, and ACE inhibitors, syntheticpolysaccharides, ticlopinin, dipyridamole, clopidogrel, fondaparinux,streptokinase, urokinase, r-urokinase, r-prourokinase, rt-PA, APSAC,TNK-rt-PA, reteplase, alteplase, monteplase, lanoplase, pamiteplase,staphylokinase, abciximab, tirofiban, orbofiban, xemilofiban,sibrafiban, roxifiban, ABT-578, CCI-779, biolimus-A9, temsirolimus,anti-CD34 antibodies, mycophenolic acid, Vitamin E, omega-3 fatty acids,tempamine, and docetaxel, an agent for altering cytochrome P450function, cyclosporine, an azole antifungal agent, itraconazole,ketoconazole, a macrolide antibiotic, clarithromycin, erythromycin,troleandomycin, an non-nucleoside reverse transcriptase inhibitor,delavirdine, a protease inhibitor, indinavir, ritonavir, saquinavir,ritonavir, grapefruit juice extract, mifepristone, nefazodone, arifamycin including rifabutin, rifampin and rifapentine, ananti-convulsant including carbamazepine, phenobarbital and phenytoin, ananti-HW agent including efavirenz and nevirapine, and an herbal agentincluding St. John's Wort, an anti-restenosis agent, ananti-thrombogenic agent, an antibiotic, an anti-platelet agent, ananti-clotting agent, an anti-inflammatory agent, an anti-neoplasticagent, a chelating agent, penicillamine, triethylene tetraminedihydrochloride, EDTA, DMSA (succimer), deferoxamine mesylate, aradiocontrast agent, a radio-isotope, a prodrug, antibody fragments,antibodies, live cells, therapeutic drug delivery microspheres ormicrobeads, gene therapy agents, viral vectors and plasmid DNA vectors.

In some embodiments, at least a portion of the ablumenal surface of thetubular member comprises a first porous layer and at a least portion ofthe lumenal surface of the tubular member comprises a second porouslayer. In some embodiments, at least a portion of the interstitial spaceof the first porous layer is preferably filled with a therapeutic agentselected from the group comprising actinomycin-D, batimistat, c-mycantisense, dexamethasone, paclitaxel, taxanes, sirolimus, tacrolimus andeverolimus. The second porous layer may be preferably filled with atherapeutic agent selected from the group comprising actinomycin-D,batimistat, c-myc antisense, dexamethasone, paclitaxel, taxanes,sirolimus, tacrolimus and everolimus, unfractionated heparin,low-molecular weight heparin, enoxaprin, synthetic polysaccharides,ticlopinin, dipyridamole, clopidogrel, fondaparinux, streptokinase,urokinase, r-urokinase, r-prourokinase, rt-PA, APSAC, TNK-rt-PA,reteplase, alteplase, monteplase, lanoplase, pamiteplase,staphylokinase, abciximab, tirofiban, orbofiban, xemilofiban,sibrafiban, roxifiban, ABT-578, CCI-779, biolimus-A9, temsirolimus,anti-CD34 antibodies, mycophenolic acid, Vitamin E, omega-3 fatty acids,tempamine, and docetaxel, an agent for altering cytochrome P450function, cyclosporine, an azole antifungal agent, itraconazole,ketoconazole, a macrolide antibiotic, clarithromycin, erythromycin,troleandomycin, an non-nucleoside reverse transcriptase inhibitor,delavirdine, a protease inhibitor, indinavir, ritonavir, saquinavir,ritonavir, grapefruit juice extract, mifepristone, nefazodone, arifamycin including rifabutin, rifampin and rifapentine, ananti-convulsant including carbamazepine, phenobarbital and phenytoin, ananti-HIV agent including efavirenz and nevirapine, and an herbal agentincluding St. John's Wort, and bivalirudin.

In one embodiment of the invention, the porous layer further comprisesat least one elution rate altering material within or about at least aportion of the interstitial space of the porous layer. The stent mayfurther comprise at least one therapeutic agent within at least aportion of the interstitial space. In some embodiments, the elution ratealtering material is distinct from the therapeutic agent. In otherembodiments, the elution rate altering material is mixed with thetherapeutic agent. The elution rate altering material may comprise adiffusion barrier or a biodegradable material or a polymer or hydrogel.In one embodiment, the porous layer further comprises a first elutionrate altering layer, a first therapeutic agent, a second elution ratealtering layer and a second therapeutic agent where the first elutionrate altering layer comprises a first elution rate altering material andthe second elution rate altering layer comprises a second elution ratealtering material. The first elution rate altering material may bedifferent from the second elution rate altering material. The firsttherapeutic agent may be different from the second therapeutic agent.The first elution rate altering layer may have an average thicknessdifferent from the average thickness of the second elution rate alteringmaterial.

In one embodiment of the invention, at least one sacrificial material isnonmetallic. At least one sacrificial material may be selected from thegroup consisting of glass, polystyrene, plastics, alumina, salts,proteins, carbohydrates, and oils. In one embodiment, at least onestructural material is nonmetallic. At least one structural material maybe selected from a list comprising silicon dioxide, silicon nitride,silicon, polystyrene, sodium chloride, and polyethylene. In someembodiments of the invention, the stent comprises a first a porous layerand a second porous layer where at least a portion of the first porouslayer is positioned between at least a portion of the second porouslayer and a portion of the tubular member. In some embodiments, theinterstitial space is configured generally by the removal of at leasttwo sacrificial materials from a mixture comprising at least twosacrificial materials and at least one structural material with thestructural material forming at least a portion of the interstitialstructural of the porous layer. The interstitial structure may compriseat least one material selected from the group consisting of gold,silver, nitinol, steel, chromium, iron, nickel, copper, aluminum,titanium, tantalum, cobalt, tungsten, palladium, vanadium, platinum,niobium, a salt, and an oxide particle. The interstitial space may beconfigured by removing at least one sacrificial material with adealloying process. The interstitial space may also be configured byremoving at least one sacrificial material with a high-pressureevaporation. In some embodiments of the stent, the therapeutic agent isloaded onto the stent through exposure to a solution containing thetherapeutic agent. In some embodiments, the therapeutic agent is loadedonto the stent in an environment less than 760 torr. In someembodiments, the solution comprises a solvent. The solvent may have ahigh solubility product for the therapeutic agent but a vapor pressureless than water. The therapeutic agent may be loaded onto the stentwhile the solvent resorbs at least some of the gaseous material withinthe interstitial space. The gaseous material may comprise the vapor formof the solvent. The therapeutic agent may be loaded onto the stent in asuper cooled environment or by use of sequential load-dry steps withsupersaturated solutions of the therapeutic agent.

In one embodiment of the invention, a therapy-eluting medical device isprovided. The device comprises at least one component of a medicaldevice having at least one therapy-eluting surface comprising aninterstitial structure and an interstitial space where the interstitialspace is configured generally by the removal of at least a portion ofone sacrificial material from a mixture comprising at least onesacrificial material in one or more structural materials that comprisethe interstitial structure of the porous layer and where thetherapy-eluting medical device is adapted to receive and release atleast one therapeutic agent. The medical device may be a stent, avascular graft, an orthopedic device, an implantable sensor housing, anartificial valve, a contraceptive device, an inter-uterine device, asubcutaneous hormonal implant, a wire coil, a neural coil, a vascularcoil for treatment of an aneurysm, a suture, a staple, a guidewire or acatheter.

In one embodiment of the invention, a therapy-eluting medical device isprovided. The device comprises at least one component of a medicaldevice having at least one therapy-eluting surface comprising aninterstitial structure and an interstitial space where the interstitialstructure and the interstitial space are configured from a precursormatrix with a directional grain structure, where the configuration isgenerally determined by the removal of at least a portion of theprecursor matrix with respect to the directional grain structure andwhere the therapy-eluting medical surface is adapted to receive andrelease at least one therapeutic agent. The medical device may be astent, a vascular graph, an orthopedic device, an implantable sensorhousing, an artificial valve, a contraceptive device, an inter-uterinedevice, a subcutaneous hormonal implant, a wire coil, a neural coil, avascular coil for treatment of an aneurysm, a suture, a staple, aguidewire or a catheter. The removal of at least a portion of theprecursor matrix is performed by at least one etchant. The configurationmay be additionally modified by a secondary etchant. The secondaryetchant may be an isotropic etchant or an anisotropic etchant.

In one embodiment of the invention, a therapy-eluting medical device isprovided. The device comprises at least one component of a medicaldevice having at least one therapy-eluting surface comprising aninterstitial structure and an interstitial space where the interstitialspace is configured generally by the removal of at least a portion ofone sacrificial material from a mixture comprising at least onesacrificial material in one or more structural materials that comprisethe interstitial structure of the porous layer and where thetherapy-eluting medical device is adapted to receive and release atleast one therapeutic agent. The medical device may be a stent, avascular graph, an orthopedic device, an implantable sensor housing, anartificial valve, a contraceptive device, an inter-uterine device, asubcutaneous hormonal implant, a wire coil, a neural coil, a vascularcoil for treatment of an aneurysm, a suture, a staple, a guidewire or acatheter.

In one embodiment of the invention, a therapy-eluting medical device isprovided. The device comprises at least one component of a medicaldevice having at least one porous coating interface comprising aninterstitial layer and an interstitial space, wherein the interstitiallayer is configured generally by the removal of at least a portion ofone sacrificial material from a mixture comprising at least onesacrificial material and one or more structural materials that comprisethe interstitial structure of the porous coating interface, and a drugeluting coating bonded to at least a portion of the porous coatinginterface. The porous coating interface may be a metallic porous coatinginterface. The porous coating interface may be nanoporous. The porouscoating interface may have an average thickness of about 0.1 microns toabout 1000 microns, and preferably about 0.1 microns to about 10microns. The porous coating interface may have an average pore size ofabout 1 nanometer to about 100 microns. In other embodiments, theaverage pore size is about 10 nanometers to about 100 microns. In stillother embodiments, the average pore size is about 0.1 to about 50nanometers. The porous layer may have an average porosity of about 1% toabout 99%, typically about 25% to about 75%, and preferably about 50% toabout 70%. In one embodiment, the porous layer has an average porosityof about 40% to about 70%. The drug eluting coating may be a polymericor hydrogel drug eluting coating. The drug of the drug eluting coatingmay be selected from a group comprising actinomycin-D, batimistat, c-mycantisense, dexamethasone, paclitaxel, taxanes, sirolimus, tacrolimus andeverolimus, unfractionated heparin, low-molecular weight heparin,enoxaprin, bivalirudin, tyrosine kinase inhibitors, Gleevec, wortmannin,PDGF inhibitors, AG1295, rho kinase inhibitors, Y27632, calcium channelblockers, amlodipine, nifedipine, and ACE inhibitors, syntheticpolysaccharides, ticlopinin, dipyridamole, clopidogrel, fondaparinux,streptokinase, urokinase, r-urokinase, r-prourokinase, rt-PA, APSAC,TNK-rt-PA, reteplase, alteplase, monteplase, lanoplase, pamiteplase,staphylokinase, abciximab, tirofiban, orbofiban, xemilofiban,sibrafiban, roxifiban, ABT-578, CCI-779, biolimus-A9, temsirolimus,anti-CD34 antibodies, mycophenolic acid, Vitamin E, omega-3 fatty acids,tempamine, and docetaxel, an agent for altering cytochrome P450function, cyclosporine, an azole antifungal agent, itraconazole,ketoconazole, a macrolide antibiotic, clarithromycin, erythromycin,troleandomycin, an non-nucleoside reverse transcriptase inhibitor,delavirdine, a protease inhibitor, indinavir, ritonavir, saquinavir,ritonavir, grapefruit juice extract, mifepristone, nefazodone, arifamycin including rifabutin, rifampin and rifapentine, ananti-convulsant including carbamazepine, phenobarbital and phenytoin, ananti-HIV agent including efavirenz and nevirapine, and also herbal agentincluding St. John's Wort, an anti-restenosis agent, ananti-thrombogenic agent, an antibiotic, an anti-platelet agent, ananti-clotting agent, an anti-inflammatory agent, an anti-neoplasticagent, a chelating agent, penicillamine, triethylene tetraminedihydrochloride, EDTA, DMSA (succimer), deferoxamine mesylate, aradiocontrast agent, a radio-isotope, a prodrug, antibody fragments,antibodies, live cells, therapeutic drug delivery microspheres ormicrobeads, gene therapy agents, viral vectors and plasmid DNA vectors.

In another embodiment of the invention, a polymer coated drug deliverystent is provided. The stent comprises a tubular metal stent body, aporous layer on the body and a drug delivery layer having a first sidewhich extends into the porous layer and a second, exposed side forreleasing a drug. In another embodiment, the stent comprises a tubularmetal stent body, a porous layer on the body, a tie layer which ismechanically bonded to the porous layer and a drug delivery layer bondedto the tie layer.

In another embodiment, the device comprises at least one component of amedical device having at least one therapy-eluting surface comprising ainterstitial structure and an interstitial space wherein theinterstitial structure and the interstitial space are configured from aprecursor matrix with a directional grain structure, wherein theconfiguration is generally determined by the removal of at least aportion of the precursor matrix with respect to the directional grainstructure. The porous layer may be adapted to absorb a range ofsubstances. In another embodiment, the porous layer is adapted tofacilitate tissue ingrowth over the porous layer. The tissue ingrowthmay result from promotion of cell anchoring. A unique aspect of oneembodiment of the invention is that the porous layer contains nanoporesof size to promote cell and tissue anchoring but below the scale knownto activate adverse cellular responses including platelet or leucocyteactivation. In some embodiments, the preferred average pore size forpromoting cell and tissue anchoring are about 1 nm to about 3000 nm, andpreferably about 20 nm to about 200 nm, or about 10 nm to about 100 nm.In some embodiments, porous layers having a peak to valley roughness ofless than about 3 microns may be associated with improved cell andtissue anchoring to the porous biomedical device. In other embodiments,a porous zone having a peak-to-valley roughness of less than about 2microns, or preferably less then 0.5 microns are used to improve celland tissue anchoring. The porous layer may also be adapted to facilitatebonding of a polymeric coating to the porous layer.

In one embodiment, a method of making a drug delivery stent is provided.The method comprises the steps of providing a stent having a poroussurface and applying a drug delivery layer to the porous surface underconditions which cause a portion of the drug delivery layer to advanceinto the porous surface to provide a bond between the porous surface andthe drug delivery layer. In another embodiment, the method comprises thesteps of bonding a tie layer to the porous surface and bonding a drugdelivery layer to the tie layer.

In another embodiment, a method of reducing the risk of delaminationbetween a stent and a polymeric drug delivery layer during balloonexpansions of the stent is provided, comprising the steps of providingthe stent with a porous surface and bonding the drug delivery layer tothe porous surface. The drug delivery layer may be bonded directly tothe stent, or bonded to a tie layer which is bonded to the stent. Inanother embodiment, the method comprises providing a stent having a drugdelivery layer, radially dilating the stent and retaining the drugdelivery layer on the stent by a plurality of links between the drugdelivery layer and pores in the stent.

In one embodiment of the invention, a therapy-eluting medical device isprovided. The device comprises at least one component of a medicaldevice having at least one porous surface comprising a interstitialstructural in an interstitial space wherein the interstitial space isconfigured generally by the removal of at least a portion of onesacrificial material from a mixture comprising at least one sacrificialmaterial in one more structural materials that comprise the interstitialstructure of the porous layer. The porous layer may be adapted to absorba range of substances. In another embodiment, the porous layer adaptedto facilitate tissue ingrowth over the porous layer.

In one embodiment, a method for manufacturing a medical device with atleast one nonpolymeric porous layer is provided. The method comprisesthe steps of providing at least a component of a medical device havingat least one surface and depositing a layer of material onto a least aportion of the surface. The layer of material comprises at least onesacrificial component and at least one structural component where atleast one component is not a polymer or a therapeutic agent. In oneembodiment, the depositing step comprises high-pressure sputtering ofthe material. The depositing step may also comprise directed vapordeposition or sintering. The material may comprise a powder or beads.The method may further comprise the step of removing at least a portionof at least one sacrificial component to form an interstitial space. Theremoving step may comprise applying a solvent to at least a portion ofat least one sacrificial component. The removing step may also compriseapplying a solvent/therapeutic agent combination to at least a portionof at least one sacrificial component. The method may further compriseapplying a magnetic field to at least a portion of the component of themedical device to at least partially orient at least one component ofthe layer of the material. The method may also further comprise varyingthe intensity or direction of the magnetic field during the depositingstep. The method may also further comprise the steps of removing atleast one sacrificial material from the layer of mix materials to form aporous layer. In some embodiments, the porous layer has a metallicstructure.

In one embodiment, a method for manufacturing a medical device with atleast one porous layer is provided. The method comprises the steps ofproviding at least a component of a medical device having at least onesurface and depositing a material onto a least a portion of the surfaceusing a high pressure to form a layer having a directional grain andremoving at least a portion of the deposited material with respect tothe directional grain to form an interstitial space. The layer ofdeposited material may comprise at least one sacrificial component andat least one structural component. In one embodiment, the removing stepcomprises applying an etchant. The etchant may be selected from thegroup comprising nitric acid, sulphuric acid, hydrofluoric acid,hydrochloric acid, ammonium fluroide, sodium hydroxide, potassiumhydroxide, or ferric chloride. The etchant is preferably nitric acid.The method may further comprise modifying the interstitial space with asecondary etchant. The secondary etchant may be an isotropic etchant oran anisotropic etchant. The removing step may also comprise applying asolvent/therapeutic agent combination to at least a portion of at leastone sacrificial component. The method may further comprise the step ofapplying a magnetic field to at least a portion of the component of themedical device to at least partially orient the depositing of thematerial with respect to the medical device. The intensity or directionof the magnetic field may be varied during the depositing step. Themethod may also further comprise the step of removing at least onesacrificial material from the layer of mix materials to form a porouslayer. In some embodiments, the porous layer has a metallic structure.The depositing step may be performed by sputtering, thermal evaporation,electron-beam evaporation, laser ablation, chemical vapor deposition,and ion beam sputtering.

In one embodiment, a method of loading a porous medical device with atherapeutic agent is provided. The method comprises the steps ofproviding at least a component of a medical device having a dealloyedporous zone. The dealloyed porous zone comprises an interstitialstructure and an interstitial space and filling at least a portion ofthe interstitial space with at least one therapeutic agent. The fillingstep may be performed by placing at least a portion of the interstitialspace of the medical device into a solution containing the therapeuticagent, spraying a solution containing the therapeutic agent onto atleast a portion of the interstitial space of the medical device, placingat least a portion of the interstitial space of the medical device intoa flow of a solution containing a therapeutic agent, or placing at leasta portion of the interstitial space of the medical device into a loadingvessel and filling the vessel with a solution containing the therapeuticagent. In one embodiment, the loading vessel is designed to minimize thedrug loading solution required for loading the biomedical device. Themethod may further comprise the step of preparing the interstitial spacefor filling with the therapeutic agent. The preparing step may alsocomprise evacuating at least a portion of any gaseous material from atleast a portion of the interstitial space. The filling step may beperformed in a sub-atmospheric environment or a vacuum environment. Thepreparing step may comprise evacuating gaseous material from at least aportion of the interstitial space by exposing at least a portion of theinterstitial space to a sub-atmospheric pressure. The preparing step maycomprise applying an electrical charge to the interstitial structure orexposing at least a portion of the interstitial structure to a gaseousmaterial. This gaseous material may comprise a solvent soluble gaseousmaterial to facilitate removal of trapped gas. The therapeutic agent ofthe filling step may also be provided in a gaseous material solublesolvent. In the form of a gaseous material soluble solvent, thetherapeutic agent causes “prewetting” of the porous structure with thegas phase of the drug loading solvent and thereby facilitates theloading process. The method may further comprise reabsorbing at least aportion of the gaseous material into the gaseous material solublesolvent. The therapeutic agent may also comprise a therapeutic substanceand a carrier. The method may further comprise precipitating thetherapeutic substance in the interstitial space. The precipitating stepmay be performed by removal of at least a portion of the carrier fromthe interstitial space. The carrier may comprise a substance selectedfrom the group consisting of an alcohol, water, ketone, a lipid, and anester. The carrier may also comprise a solvent where the solvent isselected from a group comprising de-ionized water, ethanol, methanol,DMSO, acetone, benzyl alcohol, and chloroform. The solvent may havesufficient solubility product for the therapeutic agent but a vaporpressure less than water. The filling step may be performed at a vaporpressure generally between the vapor pressure of the solvent but lessthan water. The method may further comprise exposing at least a portionof the interstitial space of the medical device to an aqueous solutionwith a low solubility product for the therapeutic agent. In someembodiments, the exposing step is performed after the filling step. Themethod may further comprise the step of exposing the device to a belowambient pressure environment for the filling step. The below ambientpressure environment may be below 760 torr, below about 380 torr, belowabout 190 torr, below about 100 torr, below about 60 torr, or belowabout 30 torr. At least a portion of the below ambient pressureenvironment may be achieved through supercooling the environment. Thelatter also permits the use of lower pressures to facilitate loadingsteps by reducing the solvent vapor pressure. After prewetting theporous structure at low temperature, the device may be mechanicallyimmersed into drug-loading solvent while at low pressure, then thepressure is gradually increased to force drug loading solution into theporous layer. Alternatively, or in addition, the method may comprise thestep of exposing the device to an above-ambient pressure environment forat least a portion of the filling step. The method may further comprisethe step of loading a propellant into the interstitial space. Thisloading step may be performed before the filling step. The method mayfurther comprise determining the amount of therapeutic agent filling theinterstitial space, changing the amount of therapeutic agent filling theinterstitial space or on the surface of the nanoporous coating. Thefilling step may be performed at the point of use or at the point ofmanufacture.

In another embodiment, a method of loading a porous medical device witha therapeutic agent is provided. The method comprises the steps ofproviding at least a component of a medical device having a nanoporouszone where the nanoporous zone comprises an interstitial structure andan interstitial space, displacing any gaseous material within theinterstitial space with a vapor form of a first solvent and filling atleast a portion of the interstitial space with at least one therapeuticagent. The filling step may be performed in a subatmospheric environmentor a vacuum environment. The method may further comprise the step ofpreparing the interstitial space for filling with the therapeutic agent.The preparing step may also comprise evacuating gaseous material from atleast a portion of the interstitial space by exposing at least a portionof the interstitial space to subatmospheric pressure. The preparing stepmay comprise applying electrical charge to the interstitial structure orexposing at least a portion of the interstitial structure to a gaseousmaterial including the gaseous or vapor phase of the solvent in which atherapeutic agent is dissolved or other gases that have a high degree ofsolubility in the loading solvent. The first solvent may be ethanol,methanol, or other loading solvent that can be vaporized underconditions compatible with integrity/viability of the therapeutic agent.The method may further comprise condensing the vapor form of the firstsolvent to a liquid form and mixing the condensed liquid form of thefirst solvent with an exogenously applied liquid form of the firstsolvent. The therapeutic agent may also comprise a therapeutic substanceand a carrier. The therapeutic agent may be loaded onto the medicaldevice by use of sequential load-dry steps with supersaturated solutionsof the therapeutic agent. The method may further comprise precipitatingthe therapeutic substance in the interstitial space. The precipitatingstep may be performed by removal of at least a portion of the carrierfrom the interstitial space. The carrier may also comprise a secondsolvent. The second solvent may be miscible with the liquid form of thefirst solvent. The second solvent may be selected from a groupcomprising de-ionized water, ethanol, methanol, DMSO, acetone andchloroform. The second solvent may have sufficient solubility productfor the therapeutic agent but a vapor pressure less than water. Thefilling step may be performed at a vapor pressure generally between thevapor pressure of the solvent but less than water. The method mayfurther comprise exposing at least a portion of the interstitial spaceof the medical device to an aqueous solution with a low solubilityproduct for the therapeutic agent. In some embodiments, the exposingstep is performed after the filling step. The method may furthercomprise the step of exposing the device to a below ambient pressureenvironment for the filling step. The below ambient pressure environmentmay be below 760 torr, below about 380 torr, below about 190 torr, belowabout 100 torr, below about 60 torr, or below about 30 torr. At least aportion of the below ambient pressure environment may be achievedthrough supercooling the environment to reduce the vapor pressure of thefirst solvent used for loading the therapeutic agent. Alternatively, orin addition, the method may comprise the step of exposing the device toan above-ambient pressure environment for at least a portion of thefilling step. The method may further comprise the step of loading apropellant into the interstitial space. This loading step may beperformed before the filling step. The method may further comprisedetermining the amount of therapeutic agent filling the interstitialspace, changing the amount of therapeutic agent filling the interstitialspace or on the surface of the nanoporous coating. The filling step maybe performed at the point of use or at the point of manufacture.

In one embodiment of the invention, a method of treating a patient isprovided. The method comprises the steps of providing a medical devicewith a nanoporous component loaded with a therapeutic agent placing themedical device at a treatment site and releasing at least a portion ofthe therapeutic agent from the porous component under active pressure.The active pressure may be generated by a propellant loaded into theporous component. The releasing step of at least a portion of thetherapeutic agent may be performed by the therapeutic agent loaded intothe porous component at a pressure higher than physiologic pressure orat a pressure of at least 180 mm Hg, 250 mm Hg or at least 300 mm Hg.

In another embodiment, a method of treating a patient is provided. Themethod comprises the steps of providing a medical device with adirectional nanoporous component loaded with a therapeutic agent placingthe medical device at a treatment site and releasing at least a portionof the therapeutic agent from the directional nanoporous component underactive pressure. The active pressure may be generated by a propellantloaded into the nanoporous component. The releasing step of at least aportion of the nanoporous agent may be performed by the therapeuticagent loaded into the nanoporous component at a pressure higher thanphysiologic pressure or at a pressure of at least 180 mm Hg, 250 mm Hgor at least 300 mm Hg.

In one embodiment, a method of treating a patient is provided. Themethod comprises the steps of providing a medical device with a porouscomponent loaded with a pro-drug placing the medical device at atreatment site releasing at least a portion of the pro-drug from theporous component and reacting the prodrug generally within the treatmentsite to form an active drug. The treatment site may be a coronary arteryor a portion of the biliary tree. Reacting step may be performed bywhite blood cells, myeloperoxidase released by white blood cells,macrophages or by renin located in the vascular wall. In someembodiments, the reacting step is performed with a reactant loaded intothe medical device. The method may further comprise removing at least aportion of the any surface deposited therapeutic agent. The method mayfurther comprise batch washing the component with a solvent with knownsolubility for the therapeutic agent or the solvent of the batch washingmay be a defined volume of solvent. The method may further comprisealtering the amount of therapeutic agent by exposing the component tocontrolled airstreams or air blasts. The method may be also be performedusing high velocity airstreams or air blasts or by controlled mechanicalwiping or by washing with one or more solvents with known solubility forthe therapeutic agent or agents. Washing step may be performed with adefined volume of at least one solvent.

In one embodiment, a device for loading porous medical devices with atherapeutic agent is provided. The device comprises a vacuum chamber, avacuum pump attached to the vacuum chamber, a therapeutic reagenthousing, a flow controller attached to the therapeutic reagent housingand porous device holder within the vacuum chamber. In some embodiments,the device further comprises a loading device designed to minimize thevolume of drug loading solutions preferably for implementing the loadingmethods described herein. The flow controller may be a controllable pumpgenerally between the therapeutic reagent housing and the porous deviceholder. In one embodiment, the flow controller comprises a hingegenerally attached to one end of the therapeutic reagent and areleasable housing support generally attached to the other end of thetherapeutic reagent housing. In one embodiment, the loading device isconfigured to minimize the volume of loading solution required to load agiven biomedical device. In another embodiment, the loading device isdesigned to optimize the flow of loading solvent to promote uniformityof loading to each device in a multidevice loading system. A preferreddesign is one that optimizes all loading parameters including drugquantities, loading volumes, and uniformity of loading between devices.

In one embodiment, a polymer coated drug delivery stent is provided. Thestent comprises a tubular metal stent body, a porous layer on the bodyand a drug delivery layer having a first side which extends into theporous layer and a second, exposed side for releasing the drug. Theporous layer may be a nanoporous layer. The porous layer may also begenerally configured by the removal of at least one sacrificial materialfrom a matrix comprising at least one sacrificial material with one ormore structural materials that comprise the porous layer. In oneembodiment, the porous layer may be a nanoporous layer. The porous layermay have an average pore size of about 1 nanometer to about 1000nanometers. In one embodiment, the porous layer is generally configuredby the removal of at least one sacrificial material from a matrixcomprising at least one sacrificial material with one or more structuralmaterials that comprises the porous layer. In another embodiment, a tielayer is mechanically bonded to the porous layer and the drug deliverylayer bonded to the tie layer.

In another embodiment, a stent for insertion into a body structure isprovided. The stent comprises a tubular member having a first end and asecond end, a lumen extending along a longitudinal axis between thefirst end and the second end, an outer surface, an inner lumenal surfaceand at least one porous layer, the porous layer comprising aninterstitial structure and an interstitial space, wherein theinterstitial space is generally configured by the removal of at least aportion of at least one sacrificial material by a thermal dealloyingprocess from a mixture comprising at least one sacrificial material withone or more structural materials that comprise the interstitialstructure of the porous layer and wherein the porous layer is adapted toreceive and release at least one therapeutic agent. At least onesacrificial material may be selected for its boiling point and/or vaporpressure. The thermal dealloying process comprises the application of aheat source. The heat source may be a light source such as a laser,infrared light source, or ultraviolet light source. The heat source mayalso be an inductive heat source or ultrasound heat source. In someembodiments, at least one sacrificial material comprises a form ofmagnesium. The application of a heat source may be performed in a vacuumof about 10⁻⁵ torr or less, 10⁻⁶ torr or less, 10⁻⁹ torr or less. Theheat source may be capable of heating a portion of the mixture to atleast about 400° C., at least about 500° C., or at least about 600° C.The porous of the pores of the porous layer may be modified by theapplication of an etchant to the porous layer. The etchant may haveanisotropic or isotropic properties.

In one embodiment, a therapy-eluting medical device is provided. Thedevice comprises at least one component of a medical device having atleast one therapy-eluting surface comprising an interstitial structureand an interstitial space, wherein the interstitial space is configuredgenerally by the removal of at least a portion of one sacrificialmaterial by a thermal dealloying process from a mixture comprising atleast one sacrificial material and one or more structural materials thatcomprise the interstitial structure of the porous layer; and wherein thetherapy-eluting surface is adapted to receive and release at least onetherapeutic agent.

In one embodiment, a method of making a drug delivery stent is provided.The method comprises the steps of providing a stent having a poroussurface, applying a drug delivery layer to the porous surface underconditions which cause a portion of the drug delivery layer to advanceinto the porous surface to provide a bond between the porous surface andthe drug delivery layer. The porous layer may be a nanoporous layer. Theporous layer may have an average pore size of about I nanometer to about1000 nanometers. In one embodiment, the porous layer is generallyconfigured by the removal of at least one sacrificial material from amatrix comprising at least one sacrificial material with one or morestructural materials that comprises the porous layer.

In one embodiment, a method of making a drug delivery stent is provided.The method comprises the steps of providing a stent having a poroussurface, bonding a tie layer to the porous surface and bonding a drugdelivery layer to the tie layer. The porous layer may be a nanoporouslayer. The porous layer may have an average pore size of about 1nanometer to about 1000 nanometers. In one embodiment, the porous layeris generally configured by the removal of at least one sacrificialmaterial from a matrix comprising at least one sacrificial material withone or more structural materials that comprises the porous layer.

In another embodiment, a method for manufacturing a medical device withat least one non-polymeric porous layer is provided, comprising thesteps of providing at least a component of a medical device having atleast one surface; and depositing a layer of a material onto at least aportion of the surface; the layer of material comprising at least onesacrificial component and at least one structural component and at leastone component is not a polymer or therapeutic agent; and thermallyremoving at least a portion of at least one sacrificial component toform an interstitial space. The method may further comprise increasingthe interstitial space with an etchant. The etchant may have isotropicproperties or anisotropic properties. The thermally removing step may beperformed in a vacuum. The thermally removing step may be performed inusing a laser.

In another embodiment of the invention, a stent for insertion into abody structure is provided, comprising a tubular member having a firstend and a second end, a lumen extending along a longitudinal axisbetween the first end and the second end, an outer surface, an innerlumenal surface; and at least one porous layer, the porous layercomprising an interstitial structure and an interstitial space whereinthe interstitial space is generally configured by the removal of atleast a portion of at least one sacrificial material from a mixturecomprising at least one sacrificial material with one or more structuralmaterials that comprise the interstitial structure of the porous layerand removal of interstitial structure with an etchant and wherein theporous layer is adapted to receive and release at least one therapeuticagent. The etchant may be an isotropic etchant or an anisotropicetchant.

In one embodiment, a method of reducing the risk of delamination betweena stent and a polymeric drug delivery layer during balloon expansion ofthe stent is provided. The method comprises providing the stent with aporous surface and bonding the drug delivery layer to the poroussurface. The porous layer may be a nanoporous layer. The porous layermay have an average pore size of about 1 nanometer to about 1000nanometers. In one embodiment, the porous layer is generally configuredby the removal of at least one sacrificial material from a matrixcomprising at least one sacrificial material with one or more structuralmaterials that comprises the porous layer. The drug delivery layer maybe bonded directly to the stent, or to the tie layer which is bonded tothe stent.

In one embodiment, a method of reducing the risk of de-laminationbetween a stent and a polymeric drug delivery layer during balloonexpansion of the stent is provided. The method comprises providing astent having a drug delivery layer, radially dilating the stent; andretaining the drug delivery layer on the stent by a plurality of linksbetween the drug delivery layer and pores in the stent. The pores may benanopores. The pores may have an average pore size of about 1 nanometerto about 1000 nanometers.

In one embodiment, a method of loading multiple therapeutic agents ontoa medical device is provided. The method comprises providing a medicaldevice with a porous surface, loading a first therapeutic agent into theporous surface, and bonding a first coating onto at least a portion ofthe porous surface, wherein the first coating comprises at least onepolymer and a second therapeutic agent. The porous surface may bedealloyed. The porous surface may also be a nanoporous surface. Themethod may further comprise bonding a second coating to at least aportion of the porous surface, wherein the second coating comprises atleast one polymer and a second therapeutic agent. The second coating mayalso be bonded to at least a portion of the first coating.

In one embodiment of the invention, an implantable medical devicecomprises at least one directional porous layer having an interstitialstructure and an interstitial space. In one embodiment, the directionalporous layer comprises a metallic precursor matrix with a directionalgrain structure that is sputtered onto the tubular member and is atleast partially configured by at least some preferential removal of thematrix with respect to the grain structure of the metallic precursormatrix. The porous layer may be adapted to receive and release at leastone therapeutic agent. The metallic precursor matrix comprises at leastone structural material and at least one sacrificial material. In oneembodiment, the filamentary porous layer further comprises a metallicprecursor matrix that is at least partially configured by the removal ofat least some of the at least one sacrificial material. In oneembodiment of the invention, the metallic precursor matrix comprises oneor more subcomponent materials selected from a list comprising L605alloy, gold, silver, nitinol, steel, chromium, iron, nickel, copper,aluminum, titanium, tantalum, cobalt, tungsten, palladium, vanadium,platinum, niobium, magnesium, a salt, oxide particle, silicon dioxide,polystyrene, and polyethylene. In one embodiment, the metallic precursormatrix preferably comprises L605 alloy. The stent may further comprise atherapeutic agent within at least a portion of the porous layer. Theremoval of matrix may be performed by at least one etchant. The etchantmay have isotropic and/or anisotropic properties.

In one embodiment, a device for treating a patient is provided. Thedevice comprises a medical device comprising a porous layer, the porouslayer having a porous volume, a first therapeutic agent within theporous layer in a concentration of at least 5 times the concentration ascalculated by the porous volume of the porous layer multiplied by thehighest concentration of the first therapeutic agent in a solventsolution. Sometimes, the first therapeutic agent within the porous layerhas a concentration of at least 10 times the concentration as calculatedby the porous volume of the porous layer multiplied by the highestconcentration of the first therapeutic agent in a solvent solution, orat least 25 times, or even at least 50 times the concentration ascalculated by the porous volume of the porous layer multiplied by thehighest concentration of the first therapeutic agent in a solventsolution. The device may further comprise a second therapeutic agentwithin the porous layer in a concentration of at least 5 times theconcentration as calculated by the porous volume of the porous layermultiplied by the highest concentration of the second therapeutic agentin a solvent solution.

In another embodiment, a method of treating a patient is provided. Themethod comprises the steps of providing a medical device with adealloyed porous component and placing the medical device at a treatmentsite. The dealloyed porous component need not contain a therapeuticagent. The porous component may also be configured for enhanced tissueingrowth, for reduced friction with adjacent tissue when implanted in alumen, for enhanced anchoring of the tubular member within a lumen, forenhanced cellular adhesion, for reduced mechanical interactions withsurrounding tissue, for reduced mechanical interactions with surroundingtissue, to comprise a degradable form of a metal configured to affectsurrounding tissue, and/or to promote tissue healing.

In one embodiment, a stent for insertion into a body structure isprovided, comprising a tubular member comprising: a first end and asecond end, a lumen extending along a longitudinal axis between thefirst end and the second end, an ablumenal surface, a lumenal surface; afirst porous layer, the first porous layer comprising a first surface, afirst interstitial structure and a first interstitial space; wherein theporous layer has a tortuosity factor of greater than about 1.1, anaverage thickness of less than 10 microns and a peak-valley surfaceroughness of less than about 2 microns. In some embodiments, the porouslayer has a tortuosity factor of greater than about 1.6. The tubularmember may further comprise a second porous layer, the second porouslayer comprising a second surface, a second interstitial structure and asecond interstitial space, or a second porous layer, the second porouslayer comprising a second interstitial structure, a second interstitialspace, and a first porous layer interface between the first porous layerand the second porous layer. The tubular member may exhibit improvedradio-opacity compared a similar tubular member lacking the first porouslayer. The average thickness of the first porous layer may be less thanabout 5 microns. The tortuosity factor of the first porous layer may bemeasured in a porous space comprising at least four pores. The firstinterstitial space may optionally have an angular component, may belocated on the outer surface of the tubular member, may be located onthe inner surface of the tubular member, may further comprise at leastone therapeutic agent within at least a portion of the interstitialspace, may be a metallic porous layer, and/or may be a nanoporous layer.In some embodiments, the nanoporous layer has an average pore diameterof less than about 200 nm, or sometimes less than about 5 nm. In someembodiments, the therapeutic agents within at least a portion of thefirst interstitial space are selected from a group comprising:actinomycin-D, batimistat, c-myc antisense, dexamethasone, paclitaxel,taxanes, sirolimus, tacrolimus and everolimus, unfractionated heparin,low-molecular weight heparin, enoxaprin, bivalirudin, tyrosine kinaseinhibitors, Gleevec, wortmannin, PDGF inhibitors, AG1295, rho kinaseinhibitors, Y27632, calcium channel blockers, amlodipine, nifedipine,and ACE inhibitors, synthetic polysaccharides, ticlopinin, dipyridamole,clopidogrel, fondaparinux, streptokinase, urokinase, r-urokinase,r-prourokinase, rt-PA, APSAC, TNK-rt-PA, reteplase, alteplase,monteplase, lanoplase, pamiteplase, staphylokinase, abciximab,tirofiban, orbofiban, xemilofiban, sibrafiban, roxifiban, ABT-578,CCI-779, biolimus-A9, temsirolimus, anti-CD34 antibodies, mycophenolicacid, Vitamin E, omega-3 fatty acids, tempamine, and docetaxel, an agentfor altering cytochrome P450 function, cyclosporine, an azole antifungalagent, itraconazole, ketoconazole, a macrolide antibiotic,clarithromycin, erythromycin, troleandomycin, an non-nucleoside reversetranscriptase inhibitor, delavirdine, a protease inhibitor, indinavir,ritonavir, saquinavir, ritonavir, grapefruit juice extract,mifepristone, nefazodone, an anti-restenosis agent, an anti-thrombogenicagent, an antibiotic, an anti-platelet agent, an anti-clotting agent, ananti-inflammatory agent, an anti-neoplastic agent, a chelating agent,penicillamine, triethylene tetramine dihydrochloride, EDTA, DMSA(succimer), deferoxamine mesylate, a radiocontrast agent, aradio-isotope, a prodrug, antibody fragments, antibodies, live cells,therapeutic drug delivery microspheres or microbeads, gene therapyagents, viral vectors and plasmid DNA vectors. The first porous layermay further comprise at least one metabolic agent within at least aportion of the interstitial space for altering the metabolization of theat least one therapeutic agent. In some embodiments, at least onemetabolic agent is a cytochrome P450 inhibitor, and sometimes the atleast one metabolic agent is ritonavir. The stent may optionally furthercomprise a polymeric coating bonded to at least a portion of the outersurface of the porous layer. The polymeric coating may be a drug elutingcoating, and may be an elution rate-controlling coating. In someinstances, the polymeric coating comprises a material selected from agroup consisting of: polyurethanes, silicones, polyesters, polyolefins,polyisobutylene, ethylene-alphaolefin copolymers, acrylic polymers andcopolymers, vinyl halide polymers and copolymers such as polyvinylchloride, polyvinyl ethers such as polyvinyl methyl ether,polyvinylidene halides such as polyvinylidene fluoride andpolyvinylidene chloride, polyacrylonitrile, polyvinyl ketones, polyvinylaromatics such as polystyrene, polyvinyl esters such as polyvinylacetate; copolymers of vinyl monomers, copolymers of vinyl monomers andolefins such as ethylene-methyl methacrylate copolymers,acrylonitrile-styrene copolymers, ABS resins, ethylene-vinyl acetatecopolymers, polyamides such as Nylon 66 and polycaprolactone, alkydresins, polycarbonates, polyoxymethylenes, polyimides, polyethers, epoxyresins, polyurethanes, rayon-triacetate, cellulose, cellulose acetate,cellulose butyrate, cellulose acetate butyrate, cellophane, cellulosenitrate, cellulose propionate, cellulose ethers, carboxymethylcellulose, collagens, chitins, polylactic acid, polyglycolic acid, andpolylactic acid-polyethylene oxide copolymers. Other coating materialsmay include lactone-based copolyesters, polyanhydrides, polyaminoacids,polysaccharides, polyphosphazenes, poly (ether-ester) copolymers, andblends of such polymers, poly (ethylene)vinylacetate,poly(hydroxy)ethylmethylmethacrylate, polyvinal pyrrolidone;polytetrafluoroethylene, cellulose esters, elastomeric polymers such assilicones (e.g. polysiloxanes and substituted polysiloxanes),polyurethanes, thermoplastic elastomers, ethylene vinyl acetatecopolymers, polyolefin. elastomers, and EPDM rubbers, EVAL,poly(hydroxyvalerate), poly(L-lactic acid), polycaprolactone,poly(lactide-co-glycolide), poly(hydroxybutyrate),poly(hydroxybutyrate-co-valerate), polydioxanone, polyorthoesters,polyanhydride, poly(glycolic acid), poly(D,L-lactic acid), poly(glycolicacid-co-trimethylene carbonate), polyphosphoesters, polyphosphoesterurethanes, poly(amino acids), cyanoacrylates, poly(trimethylenecarbonate), poly(iminocarbonate), co-poly(ether-esters) (e.g. PEO/PLA),polyalkylene oxalates, polyphosphazenes, biomolecules (such as fibrin,fibrinogen, cellulose, starch, collagen and hyaluronic acid),polyurethanes, silicones, polyesters, polyolefins, polyisobutylene andethylene-alphaolefin copolymers, acrylic polymers and copolymers, vinylhalide polymers and copolymers (such as polyvinyl chloride),polyvinylidene halides (such as polyvinylidene fluoride andpolyvinylidene chloride), polyvinyl ethers (such as polyvinylmethyl-ether), polyacrylonitrile, polyvinyl ketones, polyvinyl aromatics(such as polystyrene), polyvinyl esters (such as polyvinyl acetate),copolymers of vinyl monomers with each other and olefins (such asethylene-methyl methacrylate copolymers, acrylonitrile-styrenecopolymers, ABS resins, and ethylene-vinyl acetate copolymers),polyamides (such as NYLON 66 and polycaprolactam), alkyd resins,polycarbonates, polyoxymethylenes, polyimides, polyethers, epoxy resins,polyurethanes, rayon, rayon-triacetate, cellulose, cellulose acetate,cellulose butyrate, cellulose acetate butyrate, cellulose nitrate,cellulose propionate, cellulose ethers, carboxymethyl cellulose,CELLOPHANE, PEG, PEG-acrylate or methacrylate, silk-elastin proteinblock-copolymer, and mixtures thereof.

In one embodiment, a device for insertion into a body is provided,comprising a biocompatible device with a porous surface having atortuosity factor of greater than about 1.1, an average thickness ofless than 10 microns and a peak-valley surface roughness of less thanabout 2 microns. In some embodiments, the porous surface has atortuosity factor of greater than about 1.6. The device may also furthercomprising at least one therapeutic agent at least partially containedwith the porous surface, and/or a means for controlling elution of thetherapeutic agent from the porous surface.

In one embodiment, a method for treating a mammal is provided,comprising providing an implantable device comprising a porous surfacewith an outer surface, an interstitial space, a tortuosity factor ofgreater than about 1.1, an average thickness of less than 10 microns anda peak-valley surface roughness of less than about 2 microns; andimplanting the implantable device into a location in the body. Thelocation in the body may be a blood vessel, a portion of thegastrointestinal tract, a portion of the genitourinary tract, at leastpartially in a bone, at least partially subcutaneous, an airway,intramuscular, intraocular, intracranial or intrahepatic. The method mayfurther comprise a therapeutic agent occupying at least a portion of theinterstitial space, and also optionally eluting the therapeutic agent.The implantable device may further comprise a polymeric topcoat on outersurface of the porous surface, and sometimes a polymeric elution-ratecontrolling topcoat on outer surface of the porous surface. Theimplantable device of the method may further comprise a secondtherapeutic agent occupying at least a portion of the interstitialspace.

In one embodiment, a method for treating a mammal is provided,comprising providing a nanoporous implantable device with a means forenhancing tissue healing; and implanting the implantable device into aspace in the body.

In another embodiment, a method for treating a mammal is provided,comprising providing a nanoporous implantable device with a means forreduced mechanical slippage and friction with surrounding tissue; andimplanting the implantable device into a location in the body.

In one embodiment, a polymer coated drug delivery stent is provided,comprising a tubular metal stent body; a porous layer on the body,wherein the pores of the porous layer have an angular component; a tielayer which is mechanically bonded to the porous layer; and a drugdelivery layer bonded to the tie layer. The porous layer may be ananoporous layer. In some embodiments, the average pore size is about 1nanometer to about 1000 nanometers. The porous layer may be generallyconfigured by the removal of at least one sacrificial material from amatrix comprising at least one sacrificial material with one or morestructural materials that comprise the porous layer.

In one embodiment, a method of making a drug delivery stent is provided,comprising the steps of providing a stent having a porous surface,wherein the pores of the porous surface have an angular component; andapplying a drug delivery layer to the porous surface under conditionswhich cause a portion of the drug delivery layer to advance into theporous surface to provide a bond between the porous surface and the drugdelivery layer. The porous surface may be a nanoporous surface and/ormay have an average pore size of about 1 nanometer to about 1000nanometers. The porous surface may be generally configured by theremoval of at least one sacrificial material from a matrix comprising atleast one sacrificial material with one or more structural materialsthat comprise the porous surface.

In one embodiment, a method of making a drug delivery stent is provided,comprising the steps of providing a stent having a porous surface,wherein the pores of the porous surface have an angular component;bonding a tie layer to the porous surface; and bonding a drug deliverylayer to the tie layer. The porous surface may be a nanoporous surface,and/or may have an average pore size of about 1 nanometer to about 1000nanometers. The porous surface may be generally configured by theremoval of at least one sacrificial material from a matrix comprising atleast one sacrificial material with one or more structural materialsthat comprise the porous surface.

In one embodiment a method of reducing the risk of delamination betweena stent and a polymeric drug delivery layer during balloon expansion ofthe stent is provided, comprising the steps of providing the stent witha porous surface, wherein the pores of the porous surface have anangular component; and bonding the drug delivery layer to the poroussurface. The porous surface may be a nanoporous surface, and/or may havean average pore size of about 1 nanometer to about 1000 nanometers. Theporous surface may be generally configured by the removal of at leastone sacrificial material from a matrix comprising at least onesacrificial material with one or more structural materials that comprisethe porous surface. In some embodiments, drug delivery layer is bondeddirectly to the stent, or to a tie layer which is bonded to the stent.

In one embodiment, a method of reducing the risk of delamination betweena stent and a polymeric drug delivery layer during balloon expansion ofthe stent is provided, comprising the steps of providing a stent havinga drug delivery layer; radially dilating the stent; and retaining thedrug delivery layer on the stent by a plurality of links between thedrug delivery layer and pores in the stent; wherein the pores of thestent have an angular component. The pores may be nanopores. The poresmay have an average pore size of about 1 nanometer to about 1000nanometers. The pores may be generally configured by the removal of atleast one sacrificial material from a matrix comprising at least onesacrificial material with one or more structural materials that compriseat least a portion of the stent.

In one embodiment, a method of bonding a polymer coating to a biomedicaldevice with nanoporous layer is provided, comprising providing apolymeric coating material; selecting a solvent to dissolve a polymericcoating material for increased penetration/wicking of polymericmaterials into a nanoporous coating; dissolving the polymeric coatingmaterial using the selected solvent; and applying the dissolvedpolymeric coating material to a nanoporous surface.

In one embodiment, a method of loading a porous medical device with atherapeutic agent is provided, comprising the steps of providing atleast a component of a medical device having a porous zone, the porouszone comprising an interstitial structure, an interstitial space, anaverage depth and an average pore diameter; displacing any gaseousmaterial within the interstitial space with a vapor form of a firstsolvent; and filling at least a portion of the interstitial space withat least one therapeutic agent. The filling step may be performed in asubatmospheric environment. The method may further comprise the step ofpreparing the interstitial space for filling with the therapeutic agent.The preparing step may comprise evacuating gaseous material from atleast a portion of the interstitial space by exposing at least a portionof the interstitial space to subatmospheric pressure, applying anelectrical charge to the interstitial structure, and/or exposing atleast a portion of the interstitial space to a gaseous material. Thefirst solvent may be ethanol, methanol, or other loading solvent thatcan be vaporized under conditions compatible with sufficientintegrity/viability of the therapeutic agent. The method may furthercomprise the step of condensing the vapor form of the first solvent to aliquid form; and mixing the condensed liquid form of the first solventwith an exogenously applied liquid form of the first solvent. Thetherapeutic agent may comprise a therapeutic substance and a carrier.The filling step may be performed by use of sequential load-dry stepswith supersaturated solutions of the therapeutic agent. The method mayfurther comprise precipitating the therapeutic substance in theinterstitial space. The precipitating step may be performed by removalof at least a portion of the carrier from the interstitial space. Themethod may also further comprise providing a polymeric coating material;dissolving the polymeric coating material using at least one solvent;applying the dissolved polymeric coating material to the porous zone;and penetrating the interstitial space of the porous zone with thedissolved polymeric coating material. The method may also furthercomprise filling at least 1% of interstitial space of the nanoporouslayer. The filling may be at least 30% of interstitial space of thenanoporous layer, or at least 60% of interstitial space of thenanoporous layer. The penetrating of the interstitial space may occur toat least 1% of the average depth of the nanoporous layer, at least 30%of the average depth of the nanoporous layer, or at least 60% of theaverage depth of the nanoporous layer. The penetrating of theinterstitial space may occur to a depth of at least about 5 times theaverage pore diameter of the nanoporous layer, at least about 10 timesthe average pore diameter of the nanoporous layer, at least about 50times the average pore diameter of the nanoporous layer, or at leastabout 100 times the average pore diameter of the nanoporous layer. Insome embodiments, the carrier comprises a second solvent. The secondsolvent may be miscible with the liquid form of the first solvent. Thesecond solvent may be selected from a group comprising de-ionized water,ethanol, methanol, DMSO, acetone and chloroform. The second solvent mayhave a sufficient solubility product for the therapeutic agent but avapor pressure less than water. The filling step may be performed at avapor pressure generally between the vapor pressure of the first solventbut less than water. The method may further comprise exposing at least aportion of the interstitial space of the medical device to an aqueoussolution with a low solubility product for the therapeutic agent. Insome embodiments, the exposing step may be performed after the fillingstep. In still other embodiments, the method may further comprise thestep of exposing the device to a below ambient pressure environment forthe filling step. The below ambient pressure environment may be belowabout 760 torr, about 380 torr, about 190 torr, about 100 torr, about 60torr, or about 30 torr. The method may further comprise the step ofsupercooling the environment to reduce the vapor pressure of the firstsolvent used for loading the therapeutic agent, exposing the device toan above ambient pressure environment for at least a portion of thefilling step, and/or loading a propellant into the interstitial space.The loading step may be performed before the filling step. The methodmay further comprise the step of determining the amount of therapeuticagent filling the interstitial space, and/or changing the amount oftherapeutic agent filling the interstitial space or on the surface ofthe nanoporous coating. The filling step may be performed at the pointof use and/or at the point of manufacture.

In one embodiment, a method for providing a crystalline form of the oneor more therapeutic agents within the nanoporous layer on a device isprovided, comprising providing a device with a nanoporous layer;exposing the device to at least one vacuum-pressure cycle; filling atleast a portion of the device with at least one supersaturated solutionof a therapeutic agent; and applying at least one supercooledenvironment to the device.

In one embodiment, a method of loading a porous medical device with atherapeutic agent is provided, comprising providing at least a componentof a medical device having a porous zone, the porous zone comprising aninterstitial structure, an interstitial space, an average depth, anaverage pore diameter and at least one therapeutic agent within at leasta portion of the interstitial space; providing a polymeric coatingmaterial; dissolving the polymeric coating material into an at least onesolvent solution; applying the dissolved polymeric coating material tothe porous zone; and penetrating the interstitial space of the porouszone with the dissolved polymeric coating material. The at least onetherapeutic agent within the interstitial space may be selected from agroup comprising: actinomycin-D, batimistat, c-myc antisense,dexamethasone, paclitaxel, taxanes, sirolimus, tacrolimus andeverolimus, unfractionated heparin, low-molecular weight heparin,enoxaprin, bivalirudin, tyrosine kinase inhibitors, Gleevec, wortmannin,PDGF inhibitors, AG1295, rho kinase inhibitors, Y27632, calcium channelblockers, amlodipine, nifedipine, and ACE inhibitors, syntheticpolysaccharides, ticlopinin, dipyridamole, clopidogrel, fondaparinux,streptokinase, urokinase, r-urokinase, r-prourokinase, rt-PA, APSAC,TNK-rt-PA, reteplase, alteplase, monteplase, lanoplase, pamiteplase,staphylokinase, abciximab, tirofiban, orbofiban, xemilofiban,sibrafiban, roxifiban, ABT-578, CCI-779, biolimus-A9, temsirolimus,anti-CD34 antibodies, mycophenolic acid, Vitamin E, omega-3 fatty acids,tempamine, and docetaxel, an agent for altering cytochrome P450function, cyclosporine, an azole antifungal agent, itraconazole,ketoconazole, a macrolide antibiotic, clarithromycin, erythromycin,troleandomycin, an non-nucleoside reverse transcriptase inhibitor,delavirdine, a protease inhibitor, indinavir, ritonavir, saquinavir,ritonavir, grapefruit juice extract, mifepristone, nefazodone, ananti-restenosis agent, an anti-thrombogenic agent, an antibiotic, ananti-platelet agent, an anti-clotting agent, an anti-inflammatory agent,an anti-neoplastic agent, a chelating agent, penicillamine, triethylenetetramine dihydrochloride, EDTA, DMSA (succimer), deferoxamine mesylate,a radiocontrast agent, a radio-isotope, a prodrug, antibody fragments,antibodies, live cells, therapeutic drug delivery microspheres ormicrobeads, gene therapy agents, viral vectors and plasmid DNA vectors.In another embodiment, the at least one therapeutic agent within theinterstitial space of the porous zone may be selected from a groupcomprising: rapamycin, a rapamycin analog, paclitaxel, a paclitaxelanalog, ABT-578, CCI-779, biolimus-A9, temsirolimus, other limus familymember, macrocyclic lactones, cell cycle inhibitor that selectivelyinhibits the G1 phase of the cell cycle, mammalian inhibitor ofrapamycin, or any agent that binds to FKBP12 and has similarpharmacological properties as rapamycin. In some embodiments, the atleast one solvent used to dissolve the polymeric material may beselected from a group comprising: ethanol, methanol, acetone,chloroform, ethyl acetate, THF, benzyl alcohol, ethyl lactate,polyethyethylene glycol, propylene dlycol, dlycerin triacetin, diacetin,acetyl triethyl citrate, ethyl lactate N-methyl-2-pyrrolidinone,buyrolactone, dimethyl isosorbide, tryethylene glycol dimethyl ether,ethoxy diglycol, glycerol, glycerol formal, dimethyl formamide, dimethylacetamide, dimethyl solfoxide, CHCL3, ketones, or alcohols. Thedissolved polymeric coating material may have a concentration in the atleast one solvent solution of about 0.1 to about 100%, or sometimesabout 0.5 to about 3%. The dissolved polymeric coating material may havea concentration in the at least one solvent solution that causes dryingof the polymer solvent solution prior to contact with the therapeuticagent-containing porous zone. The method may further comprise setting adistance between a deposition device used to apply the dissolvedpolymeric coating material and the porous zone at about 1 mm to about 20cm, but sometimes between about 0.5 cm and about 5 cm. The method mayalso further comprise setting a flow rate for a deposition device usedto apply the dissolved polymeric coating material to the porous zonebetween about 0.001 and 1.0 ml/min, or between about 0.010 and about0.075 ml/min.

In one embodiment, a stent for insertion into a body structure isprovided, comprising a tubular member having a first end and a secondend, a lumen extending along a longitudinal axis between the first endand the second end, an ablumenal surface, a lumenal surface; and atleast one porous layer, the porous layer comprising an interstitialstructure and an interstitial space; wherein the interstitial space maybe generally configured by the removal of at least a portion of at leastone sacrificial material by a thermal dealloying process from a mixturecomprising at least one sacrificial material with one or more structuralmaterials that comprise the interstitial structure of the porous layer;and wherein the porous layer may be adapted to receive and release atleast one therapeutic agent. In some embodiments, at least onesacrificial material may be selected for its boiling point and/or itsvapor pressure. The thermal dealloying process may comprise theapplication of a heat source, a light source, a laser, an infrared lightsource, or an ultraviolet light source. The heat source may be aninductive heat source and/or an ultrasound source. In some embodiments,at least one sacrificial material comprises a form of magnesium. Theapplication of a heat source may be performed in a vacuum of about 10⁻⁵torr or less, or about 10⁻⁶ torr or less about 10⁻⁹ torr or less. Theheat source may be capable of heating a portion of the mixture in atemperature of at least about 400° Celsius, about 500° Celsius, or about600° Celsius. The pores of the porous layer may be modified by theapplication of an etchant to the porous layer. In some embodiments, theetchant may have anisotropic properties or isotropic properties.

In one embodiment, a erapy-eluting medical device is provided,comprising at least one component of a medical device having at leastone therapy-eluting surface comprising an interstitial structure and aninterstitial space, wherein the interstitial space may be configuredgenerally by the removal of at least a portion of one sacrificialmaterial by a thermal dealloying process from a mixture comprising atleast one sacrificial material and one or more structural materials thatcomprise the interstitial structure of the porous layer; and wherein thetherapy-eluting surface may be adapted to receive and release at leastone therapeutic agent.

In another embodiment, a method for manufacturing a medical device withat least one non-polymeric porous layer is provided, comprising thesteps of:.providing at least a component of a medical device having atleast one surface; depositing a layer of a material onto at least aportion of the surface; the layer of material comprising at least onesacrificial component and at least one structural component and at leastone component may be not a polymer or therapeutic agent; and thermallyremoving at least a portion of at least one sacrificial component toform an interstitial space. The method may further comprise increasingthe interstitial space with an etchant. The etchant may have isotropicproperties or anisotropic properties. The thermally removing step may beperformed in a vacuum. The thermally removing step may also be performedin using a laser.

In one embodiment, a stent for insertion into a body structure isprovided, comprising a tubular member having a first end and a secondend, a lumen extending along a longitudinal axis between the first endand the second end, an ablumenal surface, a lumenal surface; at leastone porous layer, the porous layer comprising a surface, an interstitialstructure and an interstitial space; and a polymeric coating bonded toat least a portion of the surface of the porous layer; wherein theinterstitial space may be generally configured by the removal of atleast one sacrificial material from a mixture comprising at least onesacrificial material with one or more structural materials that comprisethe interstitial structure of the porous layer. The porous layer mayfurther comprise at least one therapeutic agent within at least aportion of the interstitial space. The porous layer may be a metallicporous layer, a nanoporous layer, and/or have an angular component. Theouter surface of the porous layer may have a peak-valley surfaceroughness of about 0.1 to about 3.0 μm. In some embodiments, the porouslayer has a tortuosity factor of greater than about 1.1, or greater thanabout 1.6. The polymeric coating may be a drug eluting coating and/or anelution rate-controlling coating. The porous layer may further compriseat least one therapeutic agent within at least a portion of theinterstitial space. The the therapeutic agents within at least a portionof the interstitial space may be selected from a group comprising:actinomycin-D, batimistat, c-myc antisense, dexamethasone, paclitaxel,taxanes, sirolimus, tacrolimus and everolimus, unfractionated heparin,low-molecular weight heparin, enoxaprin, bivalirudin, tyrosine kinaseinhibitors, Gleevec, wortmannin, PDGF inhibitors, AG1295, rho kinaseinhibitors, Y27632, calcium channel blockers, amlodipine, nifedipine,and ACE inhibitors, synthetic polysaccharides, ticlopinin, dipyridamole,clopidogrel, fondaparinux, streptokinase, urokinase, r-urokinase,r-prourokinase, rt-PA, APSAC, TNK-rt-PA, reteplase, alteplase,monteplase, lanoplase, pamiteplase, staphylokinase, abciximab,tirofiban, orbofiban, xemilofiban, sibrafiban, roxifiban, ABT-578,CCI-779, biolimus-A9, temsirolimus, anti-CD34 antibodies, mycophenolicacid, Vitamin E, omega-3 fatty acids, tempamine, and docetaxel, an agentfor altering cytochrome P450 function, cyclosporine, an azole antifungalagent, itraconazole, ketoconazole, a macrolide antibiotic,clarithromycin, erythromycin, troleandomycin, an non-nucleoside reversetranscriptase inhibitor, delavirdine, a protease inhibitor, indinavir,ritonavir, saquinavir, ritonavir, grapefruit juice extract,mifepristone, nefazodone, an anti-restenosis agent, an anti-thrombogenicagent, an antibiotic, an anti-platelet agent, an anti-clotting agent, ananti-inflammatory agent, an anti-neoplastic agent, a chelating agent,penicillamine, triethylene tetramine dihydrochloride, EDTA, DMSA(succimer), deferoxamine mesylate, a radiocontrast agent, aradio-isotope, a prodrug, antibody fragments, antibodies, live cells,therapeutic drug delivery microspheres or microbeads, gene therapyagents, viral vectors and plasmid DNA vectors. In some embodiments, thetherapeutic agents within at least a portion of the interstitial spacemay be selected from a group comprising: rapamycin, a rapamycin analog,paclitaxel, a paclitaxel analog, ABT-578, CCI-779, biolimus-A9, ortemsirolimus. The porous layer may have an average thickness of about 5nm to about 10 microns. The porous layer may have average pore size ofabout 0.1 nanometers to about 10 microns, or about 0.1 nm to about 500nm, or sometimes about 1 nm to about 50 nm. In some embodiments, thepolymeric coating comprises a material selected from a group consistingof: polyurethanes, silicones, polyesters, polyolefins, polyisobutylene,ethylene-alphaolefin copolymers, acrylic polymers and copolymers, vinylhalide polymers and copolymers such as polyvinyl chloride, polyvinylethers such as polyvinyl methyl ether, polyvinylidene halides such aspolyvinylidene fluoride and polyvinylidene chloride, polyacrylonitrile,polyvinyl ketones, polyvinyl aromatics such as polystyrene, polyvinylesters such as polyvinyl acetate; copolymers of vinyl monomers,copolymers of vinyl monomers and olefins such as ethylene-methylmethacrylate copolymers, acrylonitrile-styrene copolymers, ABS resins,ethylene-vinyl acetate copolymers, polyamides such as Nylon 66 andpolycaprolactone, alkyd resins, polycarbonates, polyoxymethylenes,polyimides, polyethers, epoxy resins, polyurethanes, rayon-triacetate,cellulose, cellulose acetate, cellulose butyrate, cellulose acetatebutyrate, cellophane, cellulose nitrate, cellulose propionate, celluloseethers, carboxymethyl cellulose, collagens, chitins, polylactic acid,polyglycolic acid, and polylactic acid-polyethylene oxide copolymers.Other coating materials may include lactone-based copolyesters,polyanhydrides, polyaminoacids, polysaccharides, polyphosphazenes, poly(ether-ester) copolymers, and blends of such polymers, poly(ethylene)vinylacetate, poly(hydroxy)ethylmethylmethacrylate, polyvinalpyrrolidone; polytetrafluoroethylene, cellulose esters, elastomericpolymers such as silicones (e.g. polysiloxanes and substitutedpolysiloxanes), polyurethanes, thermoplastic elastomers, ethylene vinylacetate copolymers, polyolefin elastomers, and EPDM rubbers, EVAL,poly(hydroxyvalerate), poly(L-lactic acid), polycaprolactone,poly(lactide-co-glycolide), poly(hydroxybutyrate),poly(hydroxybutyrate-co-valerate), polydioxanone, polyorthoesters,polyanhydride, poly(glycolic acid), poly(D,L-lactic acid), poly(glycolicacid-co-trimethylene carbonate), polyphosphoesters, polyphosphoesterurethanes, poly(amino acids), cyanoacrylates, poly(trimethylenecarbonate), poly(iminocarbonate), co-poly(ether-esters) (e.g. PEO/PLA),polyalkylene oxalates, polyphosphazenes, biomolecules (such as fibrin,fibrinogen, cellulose, starch, collagen and hyaluronic acid),polyurethanes, silicones, polyesters, polyolefins, polyisobutylene andethylene-alphaolefin copolymers, acrylic polymers and copolymers, vinylhalide polymers and copolymers (such as polyvinyl chloride),polyvinylidene halides (such as polyvinylidene fluoride andpolyvinylidene chloride), polyvinyl ethers (such as polyvinylmethyl-ether), polyacrylonitrile, polyvinyl ketones, polyvinyl aromatics(such as polystyrene), polyvinyl esters (such as polyvinyl acetate),copolymers of vinyl monomers with each other and olefins (such asethylene-methyl methacrylate copolymers, acrylonitrile-styrenecopolymers, ABS resins, and ethylene-vinyl acetate copolymers),polyamides (such as NYLON 66 and polycaprolactam), alkyd resins,polycarbonates, polyoxymethylenes, polyimides, polyethers, epoxy resins,polyurethanes, rayon, rayon-triacetate, cellulose, cellulose acetate,cellulose butyrate, cellulose acetate butyrate, cellulose nitrate,cellulose propionate, cellulose ethers, carboxymethyl cellulose,CELLOPHANE, PEG, PEG-acrylate or methacrylate, silk-elastin proteinblock-copolymer, and mixtures thereof.

In one embodiment, a stent for insertion into a body structure isprovided, comprising a tubular member having a first end and a secondend, a lumen extending along a longitudinal axis between the first endand the second end, an ablumenal surface, an lumenal surface; at leastone porous layer, the porous layer comprising a surface, an interstitialstructure and an interstitial space; and a means for therapeutic agentelution control; wherein the interstitial space may be generallyconfigured by the removal of at least one sacrificial material from amixture comprising at least one sacrificial material with one or morestructural materials that comprise the interstitial structure of theporous layer.

In another embodiment, a therapy-eluting medical device is provided,comprising at least one component of a medical device having at leastone porous coating interface comprising an interstitial structure and aninterstitial space, wherein the interstitial structure may be configuredgenerally by the removal of at least a portion of one sacrificialmaterial from a mixture comprising at least one sacrificial material andone or more structural materials that comprise the interstitialstructure of the porous coating interface; and a polymeric coatingbonded to at least a portion of the porous coating interface. Thepolymeric coating may be a drug-eluting coating and/or an elution ratecontrolling coating. The porous coating interface may further compriseat least one therapeutic agent.

The above embodiments and methods of use are explained in more detailbelow.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is an electron micrograph of a polymeric drug-elution coatingfollowing expansion of a prior art device.

FIG. 2 is another electron micrograph of a polymeric drug-elutioncoating of a prior art device.

FIG. 3 is a perspective schematic view of an implantable stent devicehaving a porous layer on the ablumenal surface according to oneembodiment of the present invention.

FIG. 4A is a perspective view of an implantable stent device having aporous layer with varying structure along the longitudinal axis; FIG. 4Bis an axial cross sectional view of two overlapping stents.

FIGS. 5 and 6 are perspective and cross sectional views of animplantable stent device having a porous layer with varyingcircumferential structure.

FIGS. 7A-7B are electron micrographs of a porous layer formed bydissolving silver from a gold silver alloy, according to one embodimentof the present invention.

FIGS. 8A-8C are schematic cross sectional side views showing a method ofmaking an implantable stent device having a porous layer, according toone embodiment of the present invention.

FIG. 9A is a schematic representation of one embodiment of a therapyloading device for a stent. FIG. 9B is an exploded view of a portion ofthe device in FIG. 9A.

FIG. 10 is graph of the elution rate of one substance loaded into aprogrammable elution surface (PES).

FIG. 11 is a graph of the elution rates of a substance using PESmaterials of different porosities.

FIGS. 12A and 12B are graphs of the elution rates for a substance usingdifferent solvents.

FIG. 13 is a graph depicting loading differences based upon loadingtime.

FIG. 14 is a graph illustrating differences in loading based uponsolvent washing of the device.

FIG. 15 is a graph showing differences in programmable elution surfaceloading based upon changes in composition and loading conditions.

FIG. 16A is a cross sectional scanning electron micrograph of a columnaror filmentary configured porous layer.

FIG. 16B is a surface view of a scanning electron micrograph of theporous layer in FIG. 16A.

FIG. 17 is a graph showing 90-day stenosis rates between a commerciallyavailable stent and a porous coated stent that does not include aneluted therapeutic agent.

FIG. 18 is another scanning electron micrograph of another embodiment ofthe invention comprising a dealloyed coating.

FIG. 19 is another scanning electron micrograph of another embodiment ofthe invention comprising a dealloyed coating.

FIG. 20 is another electron micrograph of another embodiment of theinvention comprising a dealloyed coating.

FIGS. 21A and 21B are electron micrographs of another embodiment of theinvention comprising a dealloyed coating.

FIGS. 22A and 22B are schematic representations of an idealizedcapillary bundle for measuring tortuosity.

FIGS. 23A and 23B are schematic representations of an isolated poreopening and an isolated pore passageway in a porous zone for measuringtortuosity.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENT

The materials typically applied as coatings to medical implants, such ashydroxyapatites, porous alumina, sintered metal powders and polymericmaterials such as poly(ethylene glycol)/poly(L-lactic acid) (PLGA), havelimitations related to coating adhesion, mechanical properties, andmaterial biocompatibility. The structural integrity of existing coatingsmay be compromised during the use of the device. For example, radialexpansion of a coronary stent may substantially disrupt the polymericcoating during deformation of the stent structure. FIG. 1 depicts cracks2 in the polymeric coating of a stent following balloon expansion.Polymeric coatings may also exhibit poor adhesion to a device evenbefore expansion. FIG. 2 illustrates a separation of the polymericcoating 4 from the stent structure 6 after removal from its package. Inboth cases, there were no unusual circumstances which would predisposethe polymeric coatings to crack or separate. One embodiment of thecurrent invention is to utilize the nanoporous coating as a means toimprove adhesion of these sorts of polymer coatings to the stentsurface. Applications of these coatings also introduce additionalcomplexity to the fabrication process, increasing overall productioncosts.

Therefore, it would be advantageous to have improved implantable medicaldevices with porous layers capable of absorbing and eluting therapeuticagents and methods for fabricating those devices. Such methods wouldideally produce a more adherent and mechanically robust porous layerwhile simplifying device manufacture and loading of therapeutic agents.Methods would also ideally provide porous layers having desired poresizes and densities. These methods would also allow for controlled andprogrammable release of therapeutic agents into bodily tissues. At leastsome of these objectives will be met by the present invention.

A. Dealloying Process

Methods of the present invention provide means for fabricating animplantable medical device having at least one porous layer or zone. Thepores may be nanopores. Generally, the methods involve providing animplantable medical device containing an alloy and removing at least onecomponent of the alloy to form the porous layer. In some embodiments, analloy may first be deposited on an implantable device and one or morecomponents of the alloy may then be removed to form the porous layer.Such methods are often referred to as “dealloying.” For a generaldescription of dealloying methods, reference may be made to “Evolutionof nanoporosity in dealloying,” Jonah Erlebacher et al., Nature 410, pp.450-453, March 2001, the entire contents of which are herebyincorporated by reference. Dealloying a layer of an implantable deviceprovides a porous layer, which may then be infused with one or moretherapeutic agents for providing delivery of an agent into a patient viathe device. Use of dealloying methods will typically provide moreadherent and mechanically robust porous layers on medical implantablesthan are currently available, while also simplifying device manufacture.Such layers may also facilitate the process of optimizing loading anddelivery of one or more therapeutic agents.

Although the following description often focuses on the example ofimplantable stent devices for use in PTCA procedures, any suitableimplantable medical device may be fabricated with methods of theinvention. Other devices may include, but are not limited to, otherstents, stent grafts, implantable leads, infusion pumps, vascular coilsfor treating aneurysms including neural coils, vascular access devicessuch as implantable ports, orthopedic screws, rods, plates and otherimplants, implantable electrodes, subcutaneous drug-elution implants,and the like. Similarly, devices fabricated via methods of the presentinvention may be used to deliver any suitable therapy or combination oftherapies in a patient care context, veterinary context, researchsetting or the like. Therapeutic agents may include, for example, drugs,genes, anti-restenosis agents, anti-thrombogenic agents, antibioticagents, anti-clotting agents, anti-inflammatory agents, cancer therapyagents, gene therapy agents, viral vectors, plasmid DNA vectors and/orthe like. In other embodiments, the porous layer may be configured tohold live cells capable of secreting therapeutic materials, includingbut not limited to proteins, hormones, antibodies, and cellularsignaling substances. Other materials for supporting the function of thelive cells may also be inserted into the porous layer, including but notlimited to glucose, hormones and other substances that acttherapeutically upon the live cells. More than one live cell type may beincluded in the porous layer. The nanoporous coating may also be used asan absorption layer to remove materials from body fluids either alone orin combination with materials placed within the coating that augmentthis process. These materials may include but are not limited to specialchemicals including but not limited to chelating agents such aspenicillamine, triethylene tetramine dihydrochloride, EDTA, DMSA(succimer) and deferoxamine mesylate, chemical modification of thecoating surface, antibodies, and microbeads or other materialscontaining cross linked reagents for absorption of drugs, toxins orother agents. Thus, the following description of specific embodiments isprovided for exemplary purposes only and should not be interpreted tolimit the scope of the invention as set forth in the appended claims.

Methods of the present invention provide a means for fabricating animplantable medical device having at least one porous layer. In oneembodiment, a method of fabricating an implantable device having aporous layer for storage and controlled release of at least onetherapeutic agent is provided. This process may include providing animplantable medical device comprising at least one alloy and removing atleast one component of the alloy to form the porous layer. In someembodiments, the component is removed to form the porous layer, leavinga biocompatible material, such as gold. In some embodiments, the medicaldevice comprises a tubular stent device having an outer surface and aninner surface. For example, the stent device may comprise a coronaryartery stent for use in a percutaneous transluminal coronary angioplasty(PTCA) procedure. In some of these embodiments, the alloy is disposedalong the outer surface of the stent or other biomedical deviceincluding orthopedic implants, surgical screws, coils, and suture wirejust to name a few.

In another embodiment, a method of fabricating an implantable devicehaving a porous layer for storage and controlled release of at least onetherapeutic agent includes providing an implantable medical devicecomprising a matrix of two or more components and removing at least onecomponent of the matrix to form the porous layer. In some embodiments,the component is removed to form the porous layer, leaving abiocompatible material.

Optionally, providing the implantable medical device may also includedepositing the alloy on at least one surface of the medical device. Invarious embodiments, the alloy may be disposed along an outer surface ofthe implantable medical device, such that a dissolving step forms theporous layer on the outer surface of the device. In some embodiments,the alloy includes one or more metals, such as but not limited to gold,silver, nitinol, steel, chromium, iron, nickel, copper, aluminum,titanium, tantalum, cobalt, tungsten, palladium, vanadium, platinum,stainless steel, cobalt chromium, and/or niobium. In other embodiments,the alloy comprises at least one metal and at least one non-metal.Optionally, before the dissolving step at least one substance may beembedded within the alloy. For example, a salt or an oxide particle maybe embedded in the alloy to enhance pore formation upon dissolution.

Dissolving one or more components of the alloy may involve exposing thealloy to a dissolving substance. For example, a stainless steel alloymay be exposed to sodium hydroxide in one embodiment. Typically, one ormore of the most electrochemically active components of the alloy aredissolved. After the dissolving step, additional processing may beperformed. For example, the device may be coated after the dissolvingstep with titanium, gold and/or platinum. Some further embodimentsinclude introducing at least one therapeutic agent into the porouslayer. For example, the therapeutic agent may be introduced by liquidimmersion, vacuum desiccation, high pressure infusion or vapor loadingin various embodiments. The therapeutic agent may be any suitable agentor combination of agents, such as but not limited to anti-restenoticagent(s) or anti inflammatory agent(s), such as Rapamycin (also known asSirolimus), Taxol, Prednisone, and/or the like. In other embodiments,live cells may be encapsulated by the porous layer, thereby allowingtransport of selected molecules, such as oxygen, glucose, or insulin, toand from the cells, while shielding the cells from the immune system ofthe patient. Some embodiments may optionally include multiple porouslayers having various porosities and atomic compositions.

In another embodiment, a method for treating a blood vessel using animplantable medical device having a porous layer with controlled releaseof at least one therapeutic agent is provided. This process includesproviding at least one implantable device having a porous layercontaining at least one therapeutic agent; and placing the device withinthe blood vessel at a desired location, wherein the device controllablyreleases at least one therapeutic agent from the porous layer afterplacement. For example, in one embodiment the desired location maycomprise an area of stenosis in the blood vessel, and at least onetherapeutic agent released from a stent may inhibit re-stenosis of theblood vessel. Again, the therapeutic agent in some embodiments may beone or more anti-restenosis agents, anti-inflammatory agents, or acombination of both. In one embodiment, the blood vessel may be acoronary artery. In such embodiments, the placing step may involveplacing the stent so as to generally contact the porous layer with atleast one treatment site such as a stenotic plaque, vulnerable plaque orangioplasty site in the blood vessel and/or an inner wall of the bloodvessel.

In still another embodiment, an implantable medical device has at leastone porous layer comprising at least one remaining alloy component andinterstitial spaces, wherein the interstitial spaces comprise at leastone removed alloy component space of an alloy, the alloy comprising theat least one remaining alloy component and at least one removed alloycomponent. Also in some embodiments, the implantable medical devicecomprises an implantable stent device having an outer surface and aninner surface, and the porous layer is disposed along the outer surface.For example, the stent device may comprise a coronary artery stent foruse in a percutaneous transluminal coronary angioplasty procedure. Asdescribed above, the alloy may comprise one or more metals selected fromthe group consisting of gold, silver, nitinol, steel, chromium, iron,nickel, copper, aluminum, titanium, tantalum; cobalt, tungsten,palladium, vanadium, platinum and/or niobium. For example, the alloy maycomprise stainless steel and the porous layer may comprise iron andnickel.

In some embodiments, one or more components that are dissolved comprisethe most electrochemically active components of the alloy. Generally,the device further includes at least one therapeutic agent disposedwithin the at least one porous layer. Any such agent or combination ofagents is contemplated. Finally, the device may include a titanium orplatinum coating over an outer surface of the device.

In one embodiment of the invention, the device contains an initialmetallic porous layer The porous layer may promote adhesion of a secondporous layer comprising a polymer or other material for storage andtimed release of one or more therapeutic substances, and may also serveas a second reservoir for that or additional therapeutic agents. Thatis, one might load one therapeutic agent in the initial porous coating,and a second therapeutic agent in the second porous layer. Thiscapability is unique, in that a major limitation of current porousmaterials, including polymers used in drug delivery stents such as theCypher® and Taxus®, is the inability to deliver more than onetherapeutic agent. One embodiment of the invention comprises a stentwith a metallic nanoporous coating with a releasable first therapeuticagent placed in the nanoporous coating. A polymeric matrix containing areleasable second therapeutic agent is bonded or adhered to the metallicnanoporous coating. The first therapeutic agent and second therapeuticagent may be the same or different. In this embodiment, the metallicnanoporous coating serves to store and release therapeutic agents and toprovide an improved bonding surface for a drug eluting coating.

In another embodiment of the invention comprises providing a metallicnanoporous coating, loading a first therapeutic agent into the coatingand applying a polymer matrix containing the same or other differenttherapeutic agent using dip coating or spray coating methods currentlyin commercial use. In this manner, one could achieve loading andcontrolled release of multiple therapeutic agents including those thathave similar or very different physical characteristics including butnot limited to size, hydrophobicity, hydrophilicity, solubility, heatsensitivities, and chemical sensitivities.

B. Example: A Nanoporous Coronary Stent

Referring now to FIG. 3, an implantable medical device fabricated bymethods of the present invention may include an elongate tubular stentdevice 10, having two or more layers 12, 14 and a lumen 16. In oneembodiment, stent device 10 includes an outer (ablumenal) porous layer12 and an inner (lumenal) non-porous layer 14. Other embodiments maysuitably include an inner porous layer 12 and an outer non-porous layer14, multiple porous layers 12, multiple non-porous layers 14, a porouscoating over an entire surface of a medical device, or any combinationof porous and non-porous surfaces, layers, areas or the like to providea desired effect. In one embodiment, for example, multiple porous layersmay be layered over one another, with each layer having a differentporosity and optimally a different atomic composition. Porous layer 12and non-porous layer 14 may have any suitable thicknesses in variousembodiments. In some embodiments, for example, a very thin porous layer12 may be desired, such as for delivery of a comparatively small amountof therapeutic agent. In another embodiment, a thicker porous layer 12may be used for delivery of a larger quantity of therapeutic agentand/or for a longer duration of agent delivery. Any suitable combinationand configuration of porous layer 12 and non-porous layer 14 iscontemplated. In one embodiment, porous layer 12 may comprise the entirethickness of stent device 10, so that the device is completely porous.Again, stent device 10 is only one example of a device with which porouslayers may be used. Other devices may not have a lumen, for example, butmay still be suitable for use in the present invention. For example, theporous layer may be provided on the threaded surface of a bone screw,with the pore size optimized to facilitate cortical or cancellous boneingrowth.

The porous layer may be configured with nonuniform properties acrossportions of the porous layer. For example, in a coronary stent device,the porous layer may be configured to hold increased or decreasedamounts of therapeutic agents at the ends of the stent, as compared tothe central portion. In procedures utilizing multiple drug elutingstents, for example in treating coronary lesions longer than can becovered with a single stent, the multiples stents are often positionedto overlap each other at the ends (so called “kissing stents”). Theoverlap results in higher amounts of therapeutic agent being eluted intothe vessel proximal to the overlap region. In this embodiment of theinvention, shown in FIG. 4A and 4B, the properties of the porous layer12 are generally different at the central region 18 compared to at leastone of the end regions 20, 22 so that uniform drug elution is maintainedacross the overlap region 24.

The properties of the porous layer which influence the elution of thetherapeutic agent include layer thickness, porosity, and tortuosity ofthe pores, which may be influenced by the manufacturing technique and bycoating composition.

In one embodiment, variations in these properties are achieved usingmasking processes which result in selective deposition of porous layerswith different properties along the length of the device. Such maskingprocesses are well known to those skilled in the art of film deposition.In another embodiment, the variation in properties is achieved by usinga layer deposition process which is inherently nonuniform. Onenon-limiting example is a thin film sputtering process with a highlynonuniform sputter yield as a function of deposition angle. Theseprocesses are well known to those skilled in the art of film deposition.

Similarly, in a coronary stent device, the porous layer may be providedwith different properties around the circumference of the stent orportions thereof. FIGS. 5 and 6 are perspective and cross sectionalviews of an implantable stent device having a porous layer 12 withvarying circumferential structures. For example, a device may have aporous layer with one set of properties around three-quarters (270degrees) of the circumferential area, and a porous layer with anotherset of properties around the remaining one-quarter (90 degrees) of thecircumferential area. In other words, the porous layer properties have afunctional dependence on the azimuthal angular position denoted as angletheta in FIGS. 5 and 6. This embodiment would be useful for treatingvessel lesions which have a corresponding angular nonuniformity, forexample vessels with an asymmetric atheromatous cap. In this case itwould be advantageous to provide increased delivery of therapeuticagents in the thicker region, and decreased delivery elsewhere. Theproperties which affect elution characteristics may be varied to controlthe total dose of the therapeutic agent delivered, or the delivery rate,or other pharmacologically relevant parameters. In one embodiment,variations in these properties are achieved using masking processeswhich result in selective deposition of porous layers with differentproperties circumferentially around the device. Such masking processesare well known to those skilled in the art of film deposition. Inanother embodiment, the variation in properties is achieved by using alayer deposition process which is inherently nonuniform; for example athin film sputtering process with a highly nonuniform sputter yield as afunction of deposition angle is inherently non-uniform. These processesare well known to those skilled in the art of film deposition.

C. Pore Layer Characteristics and Features

The properties of the porous layer can be varied over large ranges. Forexample, the porous layer thickness may range from about 5 nanometers toabout 500 micrometers or more. In other embodiments, the porous layerthickness is preferably about 100 nm to about 500 μm, and in otherembodiments, about 50 nm to about 10 μm. Methods for controlling theporous layer thickness are well known to those skilled in the art offilm deposition. In one embodiment, the porous layer thickness iscontrolled by limiting the time period over which a thin film issputtered onto the device. Pore sizes may range from about 5 nanometersup to nearly the thickness of the film. Preferably, the pore sizes rangefrom about 5 nanometers to about 1,000 nanometers. In other embodiments,the pore size may be in the range of about 0.1 nm to about 500 nm ormore, sometimes from about 20 nm to about 200 nm, or from about 80 nm toabout 500 nm, and at other times about 1 nm to about 50 nm. Control ofthe pore sizes may be adjusted by controlling the amount of thesacrificial material incorporated into the layer. In one embodiment,this control is achieved by adjusting the relative rates of sputterdeposition of the porous layer material and the sacrificial material.The distribution of pore sizes may also vary. In one embodiment, thiscontrol is achieved by utilizing multiple sacrificial materials, forexample, copper, silver, and/or aluminum. The average porosity of theporous layer can be characterized by a void fraction, defined as thefraction of open volume occupied by the pores. Porous layers with highervoid fractions can deliver larger amounts of therapeutic agents for thesame thickness. Preferably, the void fraction is between about 10% toabout 80%. In some embodiments, the void fraction is preferably withinthe range of about 20% to about 60%. The void fraction may also varyacross different portions of the porous layer. These features of theporous layer may be measured using any of a variety of pore analysisproducts, such as those manufactured by Porous Materials, Inc. (Ithaca,N.Y.).

In one embodiment, different drugs, different volume of drugs, ordifferent drug activities or concentrations may be loaded in differentregions of the stent or biomedical device by use of unique vacuum diploading procedures described in greater detail later in thisapplication. For example, one could use masking techniques toselectively load the middle region versus the end regions of a stentwith different therapeutic agents. In addition, one can exploit thedifferential solubility properties of therapeutic agents in solvents inconjunction with different viscosities and wetting properties toselectively load drugs on the inside versus outside layers of thecoating. For example, one could load a hydrophobic drug like rapamycindeep into the coating using a solvent like ethanol that has highrapamycin solubility, but very low viscosity. This process could then befollowed by loading a hydrophilic drug in water solvent on the surface(the water solvent will not dissolve the rapamycin deeper in thecoating), and/or using a second hydrophobic drug in a viscous solventlike benzyl alcohol that only “wets” the upper layers of the coating. Insome embodiments of the invention, one or more therapeutic agents mayalso be applied onto the surface of the stent or biomedical device, inaddition to any therapeutic agents loaded within the porous layer of thestent or biomedical device. The surface therapeutic agent may be appliedby dip coating or spray coating. The therapeutic agent may be applied ina solvent carrier, which is then evaporated from the surface toconcentrate and/or adhere the therapeutic agent to the device surface.The therapeutic agent may also applied to the surface of the device in apolymeric carrier. In short, there are a large number of uniquecombinations of loading solvents and procedures that can be used tocontrol loading of multiple therapeutic substances into the nanoporouscoating or programmable elution surface (PES).

As mentioned above, any medical device may be fabricated with one ormore porous layers 12 according to embodiments of the present invention.Where the device is an implantable stent device 10, any suitable type,size and configuration of stent device may be fabricated with one ormore porous layers 12. In one embodiment, stent device 10 comprises anexpandable stent for implantation in a coronary artery during a PTCAprocedure. Such a stent device 10 may be fabricated from any suitablematerial or combination of materials. Referring back to FIG. 3, in oneembodiment, stent device 10 comprises a stainless steel non-porous layer14 and an iron and nickel porous layer 12. In some embodiments, porouslayer 12 may be formed of a biocompatible material, such as gold. Inother embodiments, porous layer 12 may be formed from a cobalt chromiumalloy such as L605. Any other suitable material or combination ofmaterials is contemplated. Furthermore, stent device 10 may include alayer or coating comprising a biocompatible material such as titanium,gold or platinum, which may provide biocompatibility, corrosionresistance or both.

Multiple porous layers containing therapeutic agents may be fabricated.The layers may have the same or different compositions and properties,and may contain the same or different drugs. In one embodiment, theloading of a therapeutic agent into a layer is performed before thefabrication of subsequent layers. This is accomplished by fabricating aporous layer according the methods already described, and then loadingthis layer with a therapeutic agent. This is followed by a step toremove excess therapeutic agent which could compromise the adhesion orintegrity of subsequent porous layers. Preferably, this step consists ofan oxygen plasma or backsputter etching step. Deposition and loading ofsubsequent layers is repeated until the final structure is obtained.

In one embodiment, a coronary stent is configured with a first porouslayer containing an antirestenotic agent, and a second porous layercontaining an antithrombotic agent. When the device is deployed, theelution of the therapeutic agents proceeds in reverse order. Thus, theantithrombotic agent, which is needed shortly after the devicedeployment, is eluted first. The antirestenotic agent is then elutedover a longer time period.

The porous layers may be fabricated with varying properties throughtheir cross section. Preferably, this is done by using different amountsof the sacrificial material at different stages of the deposition of thecomposite matrix. In one embodiment, a larger amount of sacrificialmaterial is used at the early stages, while a smaller amount is usedtowards the end of the matrix deposition. After the sacrificial etchprocessing, the porosity of the top of the film is less than that of thebottom. This allows a larger amount of therapeutic agent to be loadedinto a given thickness of a porous layer, while retaining the slowelution characteristics of a small pore size.

In another embodiment, the pore size is varied such that a region ofsmall pores is sandwiched between regions with large pores. This permitsthe device to have both rapid short term elution of a therapeutic agent,which elutes from the top region with large pores, and a longer, slowelution of a therapeutic agent whose rate is controlled by transport ofthe agent from the lower region of large pores by the intermediateregion of small pores.

In another embodiment, a medical device such as a vascular stentincorporates porous layers with different properties on the inner andouter surfaces. The layers may be fabricated sequentially. For examplethe inner layer is deposited after coating the outside surface with amasking material which prevents the porous layer from adhering to theoutside surface. Preferably, this masking material is photoresistant.After the inner surface is coated with the porous layer, the outersurface of the device is coated with a porous layer with differentcharacteristics using the same technique. The different coatings permitthe delivery of therapeutic agents with controlled rates and doses. Inanother embodiment, a vascular stent with a coating on the outsidesurface permits elution of an antirestenotic agent over a short periodof time, preferably one week to one month, while the coating on theinner surface permits elution of an antirestenotic agent over a longerperiod of time, preferably one month or longer.

In yet another embodiment, a medical device such as a vascular stentincorporates porous layers with the same or different properties on theinner and outer device surfaces. The inner and outer surfaces are thenloaded with different therapeutic agents. For example, an antithromboticagent such as Plavix or heparin may be loaded on the inner (lumenal)surface, and an antirestenotic agent such as rapamycin or taxol may beloaded on the outer (ablumenal) surface. When deployed, theantirestenotic agent is eluted largely towards the vessel wall. Theantithrombotic agent loaded into the porous layer on the inner surfaceof the device, which is in proximity to the blood flow, elutes towardsthe flow and reduces the risk of thrombotic events. Loading of differenttherapeutic agents onto the inner and outer surfaces is accomplished bysequential loading of each surface while the other surface is masked.

The deposition of a matrix containing the porous layer material and asacrificial material can be accomplished by any of several techniqueswhich result in robust layers exhibiting good adhesion to the medicaldevice. Preferably, this deposition is accomplished by thin filmsputtering techniques. Other methods for forming the matrix includethermal evaporation, electron-beam evaporation, high pressuresputtering, high pressure evaporation, directed vapor deposition,electroplating, laser ablation, bead sintering methods, sol-gelprocessing, aerosol processing, and combinations of these methods. Thesemethods for film deposition are well known to those skilled in the artof many disparate fields, including microelectronics fabrication,thermal barrier coating technology, and compact disc manufacturing.Descriptions of these processes can be found in standard texts, forexample “Thin Film Processes” by John L. Vossen and Werner Kern;“Silicon VLSI Technology: Fundamentals, Practice, and Modeling” by JamesD. Plummer, Michael D. Deal, and Peter B. Griffin; “Silicon Processingfor the VLSI Era” by Stanley Wolf and Richard N. Tauber.

In one embodiment, the deposited matrix includes at least oneferromagnetic material and least one nonferromagnetic material.Preferably the ferromagnetic material is nickel. This matrix depositionis preferably performed using a thin film sputtering technique. Themicroscopic or nanoscopic orientation of the ferromagnetic species iscontrolled by immersing the medical device in a magnetic field.Preferably, this magnetic field is generated by an electromagnet.Increasing the magnetic field intensity will cause a correspondingvariation in the agglomeration of the ferromagnetic material. Preferablythe ferromagnetic material is the sacrificial component of the matrix.Subsequent etching of the sacrificial material from the matrix will forma porous layer whose characteristics are controlled by the intensity anddirection of the magnetic field.

In one embodiment, the magnetic field is oriented parallel to thedirection of growth of the matrix material. The agglomeration of thesacrificial ferromagnetic material at the microscale or nanoscale causesthe pores in the porous layer to be largely oriented normal to thedirection of growth. In another embodiment, the magnetic field isoriented perpendicular to the direction of growth of the matrixmaterial. The agglomeration of the sacrificial ferromagnetic material atthe microscale or nanoscale causes the pores in the porous layer to belargely oriented perpendicular to the direction of growth. Elution ofthe therapeutic agent can be alternatively increased or decreased byusing these embodiments. In yet another embodiment, the direction of themagnetic field is varied from parallel to perpendicular at least onetime during the growth of the matrix. The agglomeration of thesacrificial ferromagnetic material at the microscale or nanoscale causesthe pores in the porous layer to be related to the variation in magneticfield, which affords an additional method for controlling the elutionrate of the therapeutic material.

The porous layer may have uniform or nonuniform characteristics at themesoscale. In this context, mesoscale is understood to be acharacteristic length several times that of the largest pores in thefilm. Preferably, the mesoscale is about ten times the size of thelargest pores. Nonuniform characteristics of a porous layer wouldcomprise layers with variations of pore size or density at themesoscale. Preferably, the variation in pore sizes or density would befrom one-tenth to unity times the size or density of the largest pores.This nonuniformity will result in corresponding variations of theelution rate of the therapeutic agent or agents. For example, a porouslayer comprising pores with size distributions centered around about 50nm and about 500 nm will have elution characteristics combining those ofseparate porous layers with the corresponding pore sizes.

In one embodiment, this distribution of pore sizes is fabricated byincorporating multiple sacrificial materials into the matrix.Preferably, the matrix is formed by thin film sputtering techniques.Preferably, the sacrificial materials are silver and aluminum. Inanother embodiment, the distribution of pore sizes is accomplished byphase segregation of the matrix material. Preferably, the matrixmaterial is a Cu/Pt alloy (75/25%) which results in a higher density ofpores in the grain boundaries between the Pt grains after dealloying, asdescribed in “Formation of nanoporous platinum Cu from Cu.0.75PtO.25” byD. V. Pugh, A. Dursun, and S. G. Corcoran, J. Mater. Res., Vol. 18, No.1, Jan 2003, pp. 216-221.

With reference now to FIGS. 7A and 7B, a porous layer 12 is shown ingreater detail. FIG. 7A is an electron micrograph (approximatemagnification of 46,000×) of one embodiment of the invention comprisinga nanoporous gold layer created by the removal of silver from asilver/gold alloy using nitric acid. FIG. 7B is a higher magnificationview (approximately 200,000×) of the nanoporous gold layer in FIG. 7A.As can be seen from the scanning electron micrographs, porous layer 12comprises structural elements interspersed with pores. In any givenembodiment, the size and density of such pores may be varied by varyingone or more elements of a method for making the device and formingporous layer 12. For example, one or more components of an alloy, asubstance used to selectively dissolve the alloy, duration time ofexposing the alloy to the dissolving substance, or the like may bechosen to give porous layer 12 certain desired characteristics. Thermalanneals prior or subsequent to the dealloying process may also beperformed to vary pore size and density. Any suitable combination ofporous layer thickness, pore size, pore density and the like iscontemplated within the scope of the present invention.

In one embodiment of the invention, an additional substance, includingbut not limited to polymers, topcoats and other material is provided inor about the porous layer to vary the elution properties of the otheragents within the porous layer. That is, whereas release kinetics fromthe PES are normally a function of diffusion limitations as defined byFick's law (i.e. J_(D)=DAdc/dx where J_(D)=diffusional flux, D=thediffusion coefficient of the diffusing substance, A=diffusion area, anddc/dx=the concentration gradient of the diffusing substance), andunstirred boundary layers (this alters dc/dx in the Fick equation)within the complex nanoporous coating, one may also include substancesin the coating that bind drugs or therapeutic agents with low or highaffinity within the coating to further control release kinetics. Forexample, release of heparin might be controlled by inclusion ofglycosaminoglycans within the pores that bind heparin and heparinsulfate at low affinity. Similarly, one may include nanoparticles coatedin such a way to bind therapeutic drugs using techniques wellestablished to one skilled in the art. Alternatively, one may alter thesurface charge of the coating to slow release through electrostaticattraction of the coating surface and an oppositely charged therapeuticagent. Some embodiments include surface coatings of materials that mayalter release properties including topcoats of polymers, hydrogels,collagen, proteoglycans, diffusion barriers, biodegradable materials,and chemically active layers. These materials may also be used incombination thereby providing virtually infinite flexibility incontrolling the kinetics of release of therapeutic agents.

In another embodiment of the invention, a method for producing a medicaldevice or component with a nanoporous layer having a directional grainis provided. In the dealloying processes previously described, theinterstitial space has a non-directional, tortuous, multi-branchingmorphology. In some instances, a nanoporous layer having directionalcharacteristic may offer different elution characteristics that arefavorable for a particular use, therapeutic agent or disease state. Inone embodiment, a columnar nanoporous layer is formed by sputtering aprecursor matrix onto a surface using a pressure of greater than about10 millitorr and preferably about 20 millitorr. The sputtering pressuremay vary depending upon the particular precursor matrix used, but thepressure is typically higher than the typical sputtering pressure and issufficient to deposit the precursor matrix with a directional grain.Other deposition processes that may be used to apply a matrix with adirectional grain include thermal evaporation, electron-beamevaporation, laser ablation, chemical vapor deposition, and ion beamsputtering. The directional grain is generally perpendicular to thedirection of deposition, but may be further altered by the applicationof magnetic fields, alteration of the sputtering angle, or both. Anetchant is then applied to the deposited matrix that preferentiallyetches between the grain boundaries of the matrix to form columnar orfilamentary structures. One example of an etchant is nitric acid, butother etchants may be used, such as sulphuric acid, hydrofluoric acid,hydrochloric acid, ammonium fluroide, sodium hydroxide, potassiumhydroxide, or ferric chloride. The precursor matrix may comprise L605alloy, gold, silver, nitinol, steel, chromium, iron, nickel, copper,aluminum, titanium, tantalum, cobalt, tungsten, palladium, vanadium,platinum, or niobium. The precursor matrix need not contain asacrificial material as described in previous embodiments of theinvention, as the directional grain of the deposited matrix cangenerally determine the flowpath of the non-specific etchant. Thisflowpath is one determinant of the morphological result of the removalprocess, rather than the chemical activity of the matrix subcomponents.The interstitial structures formed by such processes have a generaldirectional characteristic, such as a filament-like or column-likestructure, but may vary in other characteristics such as diameter orwidth, length, cross sectional shape, angle with respect to the base andspacing from other filament or column-like structures. The structuresmay be generally straight, curved or any combination thereof and stillhave a general directional characteristic. The structures may also begrouped in various shapes, numbers of structures and/or other features.Each group of structures may have different characteristics.

In other embodiments, a precursor matrix with one or more sacrificialmaterials is provided and one or more etchants are used to removematerial from the matrix. The etchant used to remove the precursormatrix along flowpaths defined by the directional grain may be the sameor different from the etchant used to remove the one or more sacrificialmaterials. The ranges of pore size, layer thickness, void fractionsother characteristics of a directional porous layer are similar to thatof the porous layers produced by the other processes described herein.

In one embodiment a precursor matrix comprising L605 alloy is sputteredonto the surface of a vascular stent surface at a pressure of about 20millitorr to a thickness of about one to two micrometers. Nitric acid isapplied to the deposited layer and then rinsed with deionized water toform a filamentary surface structure as depicted in FIG. 16A. FIG. 16Bis a SEM of the surface of the nanoporous layer of FIG. 16A.

As mentioned previously, multiple porous layers may be applied to thesurface of a medical device. The columnar/filamentary process may beused to apply multiple columnar/filamentary porous layers to a device.The columnar/filamentary process may also be combined with a dealloyingprocess to produce a multi-layered porous device having at least onelayer with a tortuous branching configuration and at least one layerwith a columnar configuration. In embodiments with three or more layers,the configurations need not be alternating. Certain multilayerconfigurations may be particularly suited for some applications of theinvention. For example, a porous layer with a columnar structure may beless prone to clogging or initiation of fibrin deposition and can bepreferentially used as the outer layer, while a noncolumnar porous layercomprises an inner layer. Alternatively, a columnar layer designed witha greater void fraction than a noncolumnar porous layer can be used asthe inner layer, in order to provide a greater therapeutic agentreservoir, while the noncolumnar outer porous layer controls the elutionrate of the therapeutic agent. One skilled in the art can selectcombinations of porous layers with differing characteristics to suit aparticular use.

In other embodiments, one may design pore sizes that approach the sizeof the eluting substance such that elution kinetics now become afunction of well defined equations for one skilled in the art relatingto restricted diffusion. Multiple combinations of the preceding methodsmay also be employed thus providing a high degree of control of elutioncharacteristics of therapeutic agents with the PES. In one embodiment ofthe invention, a medical device comprises a drug-eluting surface or zonehaving an average pore size of about 2 times to about 400 times themaximum diameter of a molecule or unit of the therapeutic agent to beeluted. Preferably, the average pore size is about 2.5 times to about200 times the maximum diameter of a molecule or unit of therapeuticagent, and most preferably about 3 times to about 50 times the maximumdiameter of a molecule or unit of the therapeutic agent. For example, adrug-eluting coronary stent with a dealloyed nanoporous surface foreluting rapamycin, which has a maximum diameter of 1.6 nanometers, maybe used with a nanoporous layer having an average pore diameter fromabout 3 nm to about 640 nm, preferably a nanoporous layer having anaverage pore diameter from about 4 nm to about 320 nm, and mostpreferably a nanoporous layer having an average pore diameter from about5 nm to about 80 nm.

Besides measures such as pore size, porous zone thickness andinterstitial volume per volume of porous layer or void fraction, ananoporous layer may be described using other measures of poremorphology that have been established or described. In addition to theability of substantially smaller pore size, the nanoporous structureresulting from a dealloying process may be produced in some embodimentswith an interconnected, tortuous pore morphology and/or a moreconsistent pore shape and pore diameter than can be achieved with otherporous structures used in medical devices. These features allow such ananoporous structure to provide a more similar drug-elution profile in asmaller porous layer or coating thickness than traditional non-polymericand polymeric drug elution structures.

In one embodiment, the tortuosity may be measured indirectly using atortuosity factor T, which is calculated by the ratio of the specificsurface area S of the porous zone to an idealized surface area So, asdepicted in FIGS. 22A and 22B, of a group of capillary bundles with apore radius equal to that of the average pore radius of the actualporous zone: $T = \frac{S}{S_{0}}$(Saripalli K P, et al. “Prediction of diffusion coefficients in porousmedia using tortuosity factors based on interfacial areas” Ground Water,2002. 40(4): p. 346-352, herein incorporated by reference) The specificsurface area So represents the expanse of surfaces within a porousmedium with which a fluid within the porous medium must contact.Typically, this surface is a more meaningful measure of the expanse offlow within the porous medium compared to linear dimensions. Thespecific surface area S₀ may be determined experimentally using BET(Brunauer, Emmett and Teller) adsorption measurements apparatuses whichare well known in the art, such as those manufactured by PorousMaterials, Inc. (Ithaca, N.Y.). The idealized surface area S₀ can becalculated using the pore volume fraction φ and the pore radius r_(p):$S_{0} = \frac{2\phi}{r_{p}}$The volume fraction of pores, φ, is the fraction of the coating volumethat is freely accessible by fluids. This parameter may be estimatedfrom optical and/or electron micrographs. The pore radius; r_(p), is theaverage pore radius determined experimentally or estimated from opticaland/or electron micrographs.

Typically, a tortuosity factor is calculated based upon a volume ofstent or coating material having a width, a depth and a length andcontaining a plurality of pore openings. Preferably, the tortuosityfactor is calculated on a volume of porous material containing at leasttwo pore openings and preferably at least three pore openings and mostpreferably at least four pore openings. Anomalous results may occur whenattempting determine the tortuosity factor based upon a single poreviewed in isolation.

Taking the silver-gold dealloyed nanoporous structure depicted in themicrographs of FIGS. 16A and 16B, for example, the tortuosity factor isestimated to be about 1.6, given the average pore radius of about 20 nmand an estimated pore volume fraction of about 0.50. Other dealloyednanoporous layers, such as those derived from L605 and magnesium alloys,are estimated to achieve a higher tortuosity factor in the range ofabout 1 to about 10, sometimes about 1.1 to about 10, and occasionally1.5 to about 5, while other embodiments may have a tortuosity factor ofabout 3.0 to about 15, or even up to a tortuosity factor of about 30.Generally, as the tortuosity factor increases, the elution rate from theporous layer decreases. The drug-elution profile of a therapeutic agentmay be controlled by altering the tortuosity of the pore structure ofthe nanoporous zone or layer. Although it is believed that increasingtortuosity by increasing the surface area may have a greater effect onelution rates, altering the specific surface area S by decreasing thepore diameter may not increase tortuosity because the idealized surfacearea will also increase. This typically maintains the tortuosity factorat about the same magnitude. The ranges of the tortuosity factordescribed above for dealloyed nanoporous layers are typically higherthan those achieved by sintering or ordered aggregation ofnanostructures, which tends to have lower void fractions because thesintered particles or nanoparticles take up most of the space, and fromdisordered aggregation of nanostructures, which often have higher voidfractions due to the poor stacking function of the nanostructures, butresult in a lower tortuosity factor because straight passageways throughthe entire thickness of the pore structure are often found throughoutthe aggregated nanostructures. Similarly, the increase in surface areaas defined by a plurality of discrete pore openings spaced about thesurface of a medical device, such as those described in U.S. Pat. No.6,379,381 to Hossainy, is far less than that achieved by a dealloyedporous zone or layer.

In one embodiment of the invention, the tortuosity factor may bemanipulated to control the elution kinetics of one or more therapeuticagents within the porous medium. For example, the diffusion coefficientof a therapeutic agent within a porous medium, D_(p), is generallyrelated to the ratio of the diffusion coefficient of the therapeuticagent in bulk solution, D_(B) over the tortuosity factor:$D_{p} = \frac{D_{B}}{T}$

Alternatively, the tortuosity of a porous structure or layer may becharacterized based upon the ratio of the length of the shortest porepathway 40 between a pore opening 42 at the surface 44 or interface ofthe porous zone and the farthest contiguous point 46 in the porestructure from the pore opening 40, and the length of the straight line48 between the pore opening 42 and same farthest contiguous point 46, asshown in FIG. 23A, or alternatively the ratio as compared to thefarthest contiguous point 50 in the pore structure that is perpendicularin depth from the pore opening 42, as shown in FIG. 23B. In someembodiments, a dealloyed porous zone will have a tortuosity ratio ofabout 1.05 to about 20.00, sometimes about 1.05 to about 5.00,preferably a tortuosity ratio of about 1.20 to about 3.00, and mostpreferably about 1.25 to about 1.75.

The pore diameter of a dealloyed porous zone can also be characterizedby the variability of the pore diameter. In some embodiments of theinvention, as shown in FIGS. 16A and 16B, the pore diameter of adealloyed porous zone has a consistency whereby the standard deviationof the average pore diameter throughout the porous zone is not more thanabout 2 times the average pore diameter, and preferably not more thanabout the average pore diameter, and most preferably no greater thanabout 0.25 times the average pore diameter. In other embodiments,however, the pore diameter may be more varied and/or irregular.

Still another parameter for characterizing the pore structure of aporous zone or coating is the pore shape. One measure of pore shape isdescribed in T. M. Cimino, A. H. Graham, T. F. Murphy ve A. Lawley, “TheEffect of Microstructure and Pore Morphology on Mechanical and DynamicProperties of Ferrous P/M Materials”, Advances in P/M & ParticulateMaterials, Proc. Int. Con., Vancouver, MPIF, 1999, Vol.2, pp.7-65/7-84,herein incorporated by reference in its entirety. The pore shapecalculated as a Form Factor related to the area of the pore (A) and thecircumference of the pore (P) in a plane on optical microscopy orscanning electron microscopy as follows:Form Factor=4πA/(P)²In some embodiments of the invention, the dealloyed porous zone has anaverage pore form factor of about 0.05 to about 1.00, sometimes about0.40 to about 0.80, or about 0.50 to about 0.80, and at other timesabout 0.10 to about 0.60, or about 0.20 to about 0.60.

A porous layer or medium may also be characterized by the roughness ofthe porous layer surface. The roughness of the surface of a porous layermay be characterized by established surface metrology standards (e.g.ASME B46.1-1995 or ISO 4287-1997, herein incorporated by reference intheir entirety) that disclose a variety of surface profile parameters.The roughness of a surface may be characterized by how a surfacedeviates from its mean line over an evaluation length. This evaluationlength is typically measured over range of about 10 microns to about 100microns, sometimes over a range of about 20 microns to about 50 microns,and occasionally over a range about 30 microns to about 200 microns. Onecommonly used parameter includes peak-valley surface roughness, R_(t),which is the total sum of the height of the highest peak from the meanline and the depth of the deepest valley from the mean line across anevaluation length. Using this measurement, a dealloyed porous zone ormedium typically has a peak-valley surface roughness of about 0.1microns to about 2.5 microns, sometimes a peak-valley surface roughnessof about 0.2 microns to about 2.0 microns, and occasionally about 0.5microns to about 1.0 microns. This and other roughness measures may bedetermined by using any of a variety of well established techniques,including white light interferometry, Atomic Force Microscopy (AFM),Scanning Electron Microscopy (SEM) stereo imaging, and Focused Ion Beam(FIB) combined with SEM imaging (cross section).

D. Manufacturing of Porous Layers

Referring now to FIGS. 8A through 8C, a method for fabricating animplantable medical device 20 having a porous layer suitably includesproviding an implantable device comprising at least a matrix of two ormore materials or components and removing at least one component of thematrix to form the porous layer. A matrix will typically have one ormore sacrificial materials and one or more structural materials, thesacrificial materials generally capable of removal by a componentremoval process while generally leaving at least one of the structuralmaterials generally intact.

As shown in the cross sectional FIG. 8A, a medical device 20 such as astent may include a precursor matrix layer 22, a substrate layer 24 anda lumen 26. Precursor matrix layer 22 can be deposited onto substratelayer 24 by various processes, including but not limited to physicalvapor deposition, ion implantation, sputter deposition, thermal orelectron beam evaporation, chemical vapor deposition, pulsed laserdeposition, or the like. Using such techniques, precursor matrix layer22 may be synthesized in situ from various materials, as describedpreviously, such that exposure to a component removal process willremove the sacrificial component of precursor matrix layer 22, leavingbehind a porous matrix. In another embodiment, precursor matrix layer 22and substrate layer 24 may be made from the same material.

As previously described, medical device 20 may comprise any suitablestent or other device and precursor matrix layer 22, substrate layer 24and/or other layers may be given any suitable configurations,thicknesses and the like. In some embodiments, precursor matrix layer 22is disposed along an outer surface of device 20, while in otherembodiments, precursor matrix layer 22 may be disposed along an innersurface, both inner and outer surfaces, or the like. The matrix used toform precursor matrix layer 22 may comprise any suitable matrix and maybe a metal, metal alloy, metal/non-metal matrix, non-metal/non-metalmatrix or a combination of three or more components. In variousembodiments, for example, components of precursor matrix layer 22 mayinclude steel, nitinol, chromium, brass, copper, iron, nickel, aluminum,titanium, gold, silver, tantalum, cobalt, tungsten, palladium, vanadium,platinum and/or niobium. In some embodiments, one or more additionalsubstances may be embedded within precursor matrix layer 22 to cause orenhance pore formation during the fabrication process. For example, asalt, an oxide particle or the like may be added to precursor alloylayer 22 to enhance pore formation.

In one embodiment, the matrix comprises gold as a structural materialand sodium chloride crystals as a sacrificial material, becoming porousafter immersion in a water bath. The size of the pores may be determinedby the dimensions of the salt crystals. Alternatively, quartz or silicondioxide nanoparticles could be used as a sacrificial materialdistributed inside a matrix employing platinum as the structuralmaterial. This matrix would form a porous platinum layer afterdissolving the quartz or silicon dioxide nanoparticles in hydrofluoricacid. It is also possible to combine nonmetallic structural materialswith nonmetallic sacrificial materials; an example would be a porouslayer of silicon nitride formed from a matrix of codeposited siliconnitride and polystyrene beads, followed by a sacrificial etch inacetone. A nonmetallic matrix employing a metallic sacrificial materialis also within the scope of this invention. An example would be a porouslayer of polydimethylsiloxane (PDMS) formed from a matrix of PDMS andnickel nanoparticles, followed by etching of the nickel in nitric acid.One skilled in the art will understand that many other combinations ofmaterials are possible.

In one embodiment, the structural layer is metallic, and the sacrificialmaterial is silicon dioxide. Preferably, the matrix is fabricated bycosputtering the structural layer metal and the silicon dioxide.Preferably, the silicon dioxide sacrificial material is sputtered from astoichiometric silicon dioxide target. Alternatively, the silicondioxide sacrificial material is reactively sputtered from a silicontarget using a sputter gas mixture containing oxygen and at least oneother gas. Preferably, the other gas is argon.

As shown in FIG. 8B, implantable medical device 20 is typically exposedto a substance or energy source (arrows) to dissolve or otherwise removeat least one component of the alloy to form the porous layer fromprecursor alloy layer 22. In various embodiments, any suitable substancemay be used for removing at least one component of the alloy. In oneembodiment, for example, the alloy comprises stainless steel, such as316L stainless steel, and dissolving at least one component of the steelcomprises exposing the steel to hot sodium hydroxide to dissolvechromium and leave iron and nickel as the porous layer. In anotherembodiment, a silver gold alloy may be exposed to nitric acid todissolve the silver and leave the gold as the porous layer (as shown inFIGS. 7A and 7B).

In another embodiment, a cobalt chromium alloy, such as L605, ismodified by the addition of a sacrificial material such as silver,copper or aluminum, which is subsequently removed by processing in anappropriate solvent, such as nitric acid, sulfuric acid or phosphoricacid, to leave a porous film of the original cobalt chromium alloy. Inanother embodiment, a platinum copper alloy is dealloyed in the presenceof sulfuric acid to produce porous platinum. In some embodiments,nitinol may be dissolved by a suitable dissolving substance to leave aporous layer. The dissolving process may include the use of electrochemical cells to bias device 20 in solution so as to facilitate thedealloying process. Any other suitable combination of alloy anddissolving or component removing substance is contemplated. Furthermore,any means for exposing medical device 20 to a dissolving substance orenergy source such as heat or energetic plasma is contemplated. Forexample, medical device 20 may be immersed in, sprayed with, coatedwith, etc. any suitable substance or combination of substances.

As shown in FIG. 8C, one or more components of precursor alloy layer 22are selectively removed to form a porous layer 23. In some embodiments,removing at least one component of the alloy comprises dissolving one ormore of the most electrochemically active components of the alloy. Forexample, in a steel alloy the chromium component may be dissolved,leaving the iron and nickel components. Additional processing of medicaldevice 20 may include introduction of one or more therapeutic agentsinto porous layer 23. Any suitable agent(s) may be introduced and theymay be introduced by any desired method. For example, methods forintroducing therapeutic agents include, but are not limited to, liquidimmersion, vacuum desiccation, high pressure infusion, vapor loading,and the like. Additional unique loading methods, or variations of thepreceding methods are described in detail elsewhere in this application.

1. Thermal Dealloying

In another embodiment of the invention, a thermal method of creating aporous layer is provided. A thermal method of removing a sacrificialmaterial may be advantageous in some situations compared to chemicalremoval with an etchant. For example, removal with an etchant may reducethe integrity of the resulting matrix layer through hydrogenembrittlement. An etchant may also affect the loading characteristics ofthe porous layer due to surface adsorbents or incomplete dealloying. Inone embodiment, a precursor matrix with one or more structural materialsand one or more sacrificial materials is deposited onto a medicaldevice. At least one sacrificial material is selected for its boilingpoint and/or vapor pressure. By thermally treating the precursor matrixon the medical device under particular conditions, at least a portion ofthe sacrificial material may be removed from the matrix. The thermalprocess may be repeated to obtain the desired degree of dealloying andto achieve the desired dealloying in thicker porous layers. Thesequential layers of porous material produced by this method can havethe same or different porosities. With materials having differentporosities, the effect of multiple intermediate thermal dealloying mayreduce interdiffusion of the sacrificial components and produce PESlayers with more abrupt transitions between porosities.

Heat sources that may be used with the thermal method include but arenot limited to infrared radiation, visible light, ultraviolet radiation,inductive heating, laser illumination, high-frequency ultrasound orcombinations thereof. Heat sources capable of raising the matrixtemperatures to between about 400° Celsius to about 500° Celsius may beused, but heat sources capable of raising matrix temperatures to about600° Celsius are preferred. Typically, thermal treatment will beperformed under a vacuum environment to reduce contamination relatedproblems from the thermal process, but this is not required. In oneembodiment, the thermal dealloying process is performed at a vacuumlevel of about 10⁻⁵ torr or less. In other embodiments, the thermaldealloying process is performed at high vacuum from about 10⁻⁶ torr toabout 10⁻⁸ torr. In still other embodiments, the thermal dealloyingprocess is performed at ultra-high vacuum conditions of about 10⁻⁹ torror less.

The thermal dealloying process, and the other processes described, canalso be performed in the presence of a reactive gas such as hydrogen,chlorine, oxygen, or a reactive plasma such as oxygen, sulfurhexafluoride, or chlorofluorocarbons. The reactive gas or plasma mayaccelerate the removal of the sacrificial material. Energy from otheroptical or acoustic sources may be applied to further alter the thermalremoval process or other removal processes.

Structural materials of the precursor matrix used for the thermaldealloying process include but are not limited to L605, stainless steel,platinum, gold, tantalum titanium, nitinol and combinations thereof.Sacrificial materials may include magnesium and indium. One skilled inthe art can select various combinations of structural and sacrificialmaterials to use as a precursor matrix. One example of a precursormatrix is L605 cosputtered with about 20% to about 40% magnesium. Theprecursor matrix may be deposited upon a heated, unheated or cooledsubstrate, but unheated substrates are preferred.

The thermal method may used in combination with one or more otherprocessing methods described herein to produce a programmable elutionsystem having the desired configuration and/or characteristics. Theorder, sequence and/or repetition of the various removal processes mayaffect the final configuration and characteristics of the porous layer.In one example, the thermal dealloying process is first used to form theinitial porous layer configuration, followed by a chemical etchingprocess which can increase the pore size of the initial porous layerconfiguration with varying degrees of specificity.

2. Modification of Nanoporous Structures

Another embodiment of the invention comprises a method for furthermodification of a porous material. An existing porous material may havepores with a characteristic dimension and density that is suboptimal forthe desired elution profile of the PES. For example, the existing porestructure may be insufficiently small for the desired elution profile.By providing a method for coarsening the structure of a porous material,a higher void fraction may be achieved. The modified structure may bebetter suited for some therapeutic uses than the original structure ofthe PES. A modification process may also simplify the manufacture of thePES by reducing the number of base structures produced during theinitial manufacturing process, which are then used to produce variationsof the PES through further modification processes. These adjuvantprocesses may remove the structural (i.e. non-sacrificial) material fromthe PES instead of limiting removal to sacrificial components of theprecursor matrix. In one example, an anisotropic etchant may be used toincrease the pore volume with further modification of general poremorphology. An anisotropic etchant removes material from the remainingporous layer at different rates along different directions in thematrix. Isotropic etchants can also be used to increase thecharacteristic dimension of the pores while maintaining the general porestructure morphology. These processes can be utilized to removeadditional sacrificial material that was isolated in the porous matrix,allow rearrangement of the microstructure, alter the mechanicalproperties of the porous film, and/or the surface related effects of aporous structure.

The processes involved in making a porous material can also influencethe other resultant properties of the material. In many dealloying andnon-dealloying processes, the surface characteristics of the precursormatrix and the corresponding porous layer or film may affect theenergetics and kinetics of the formation of resulting porous material.In some embodiments of the invention, the desired features of the porousmaterial originate less from the contribution of material propertiesfrom the bulk material and more from the influence of surface relatedeffects. For instance, the particular surface effects or states of aporous layer may be advantageous in loading, retaining or eluting atherapeutic agent. In some embodiments, the surface states for a givenporous material may be affected by crystallographic projections andassociated surface terminations throughout the porous material. Surfacestates can have specific energetics related to the physical structure,composition, and environmental history of the porous material. Throughthe use of chemical and thermal processes, the surface of the porousmaterial can be tailored for the desired chemisorption or physisorptionproperties. This tailoring may be performed with etchants having variousproperties. Isotropic etchants are indiscriminate in the removal ofatomic species and leave the surface characteristics of the porous layerrelatively unchanged, while anisotropic etchants can preferentiallyremove material from a subset of orientations thereby skewing thedistribution of surface states. Under some thermal and chemicalprocesses, the physical arrangement of atoms on the surface can bealtered or undergo surface reconstruction. Surface reconstruction withthermal and chemical processes can be used to control the retention orrelease of the drug.

In some embodiments, a protective layer or coating may be formed oradded to medical device 20, such as a titanium, gold or platinum layeror coating. If there is a concern that porous layer 23 may not bebiocompatible, a passivation layer may be deposited into porous layer 23to enhance biocompatibility. For instance, a very thin layer of gold maybe electroplated into the dealloyed porous layer 23. Electrolessdeposition may also be used to achieve the same effect. Depending on thecomposition of porous layer 23, the porous coating may also bepassivated chemically or in a reactive ion plasma.

E. Use of Therapeutic Agents With a Porous Layer

Any implantable medical device of the present invention may include oneor more therapeutic agents disposed within one or more porous layers 12.As discussed above, any agent or combination of agents may be included.Additionally, as described further below, any suitable method forintroducing an agent into a porous layer may be used.

The porous layer or layers of a medical device may be loaded with one ormore of any of a variety of therapeutic agents, including but notlimited to drug compounds, hormones, pro-hormones, vitamins, ananti-restenosis agent, an anti-thrombogenic agent, an antibiotic, ananti-platelet agent, an anti-clotting agent, an anti-inflammatory agent,a chelating agent, small interfering RNAs (siRNAs), morpholinos,antisense oligonucleotides, an anti-neoplastic agent, a radiocontrastagent, a radio-isotope, an immune modulating agent, a prodrug, antibodyfragments, antibodies and live cells, actinomycin-D, batimistat, c-mycantisense, dexamethasone, paclitaxel, taxanes, sirolimus, tacrolimus andeverolimus, unfractionated heparin, low-molecular weight heparin,enoxaprin, hirudin, bivalirudin, tyrosine kinase inhibitors, Gleevec,wortmannin, PDGF inhibitors, AG1295, rho kinase inhibitors, Y27632,calcium channel blockers, amlodipine, nifedipine, and ACE inhibitors,synthetic polysaccharides, ticlopinin, dipyridamole, clopidogrel,fondaparinux, streptokinase, urokinase, r-urokinase, r-prourokinase,rt-PA, APSAC, TNK-rt-PA, reteplase, alteplase, monteplase, lanoplase,pamiteplase, staphylokinase, abciximab, tirofiban, orbofiban,xemilofiban, sibrafiban, and roxifiban. Therapeutic drug deliverymicrospheres as described by Unger et al. in U.S. Pat. No. 5,580,575 andvectors for performing localized gene therapy are also usable with theporous layers. These vectors may include viral vectors and plasmid DNAvectors.

Other suitable therapeutic substances may include other glucocorticoids(e.g. betamethasone), angiopeptin, aspirin, growth factors,oligonucleotides, and, more generally, antimitotic agents, antioxidants,antimetabolite agents, and anti-inflammatory agents could be used.Antimitotic agents and antimetabolite agents can include drugs such asABT-578, CCI-779, biolimus-A9, temsirolimus, methotrexate, azathioprine,vincristine, vinblastine, 5-fluorouracil, adriamycin and mutamycin.Antibiotic agents can include penicillin, cefoxitin, oxacillin,tobramycin, and gentamycin. Other specific agents may include anti-CD34antibodies, mycophenolic acid, Vitamin E, omega-3 fatty acids,tempamine, docetaxel, an agent for altering cytochrome P450 function,cyclosporine, an azole antifungal agent, itraconazole, ketoconazole, amacrolide antibiotic, clarithromycin, erythromycin, troleandomycin, annon-nucleoside reverse transcriptase inhibitor, delavirdine, a proteaseinhibitor, indinavir, ritonavir, saquinavir, ritonavir, grapefruit juiceextract, mifepristone, nefazodone, a rifamycin including rifabutin,rifampin and rifapentine, an anti-convulsant including carbamazepine,phenobarbital and phenytoin, an anti-HIV agent including efavirenz andnevirapine, and an herbal agent including St. John's Wort. Thetherapeutic agent may also be any macrocyclic lactone, any cell cycleinhibitor that acts selectively at a G1 phase of a cell cycle,inhibitors of cyclin dependent kinases involved with progression of cellcycle through the G1 phase of the cell cycle, any one or more of a groupof flavopiridol and its structural analogs, agents that elevateendogenous P27 kinase, inhibiting protein, staurosporin and relatedsmall molecules, protein kinase inhibitors including the class oftyrphostins that selectively inhibit protein kinase to antagonize signaltransduction in smooth muscle in response to a range of growth factors,an inhibitor of mammalian target of rapamycin, or any agent that is ananalog or congeners that binds a high affinity cytosolic protein, FKBP12 and possesses the same or similar pharmacologic properties asrapamycin.

In one embodiment, the drugs or biologically active materials which canbe used in the invention can be any therapeutic substances such as thosewhich reduce or prevent adverse physiological reactions from exposingbody tissue to the medical device. In one specific embodiment, the drugsincorporated into the porous layer are substantially free of ionicsurfactants. The drugs may be of various physical states, e.g.,molecular distribution, crystal forms or cluster forms.

In another embodiment of the invention, a medical device or stent with aporous zone is provided with a first therapeutic agent for treating thetissue or vessel about the medical device or stent, along with a secondagent for altering the degradation, uptake or other pharmacologicalproperty of the first therapeutic agent. In one example, the tissue orblood concentrations of the first therapeutic agent may be alteredthrough changes in the cytochrome P450 enzyme system that is ofteninvolved in the metabolism of drugs. Although the cytochrome P450 systemis typically identified with the liver, there is also evidence that thesystem has significant activity in the enterocytes of the smallintestine and the endothelial and smooth muscle cells of a vessel wall,in particular the CYP3 family of cytochrome P450 genes. Other cytochromeP450 genes, such as the CYP 1, CYP2 and CYP4 families, may also beinvolved. For a particular therapeutic agent, one or multiple familiesof cytochrome P450 enzyme may be involved in the metabolism of thatagent. In a preferred embodiment, a therapeutic agent that ismetabolized by the cytochrome P450 system may be used in combinationwith an inhibitor of the cytochrome P450 system including but notlimited to cyclosporine, an azole antifungal agent, itraconazole,ketoconazole, a calcium channel blocker, diltiazem, verapamil, amacrolide antibiotic, clarithromycin, erythromycin, troleandomycin, annon-nucleoside reverse transcriptase inhibitor, delavirdine, a proteaseinhibitor, indinavir, ritonavir, saquinavir, ritonavir, aselective-serotonin reuptake inhibitor, fluoxetine, an H₂ receptorantagonist, cimetidine, an herbal medicine, grapefruit juice extract,mifepristone, and nefazodone. Note, however, the use of these agents ina therapy eluting medical device may not be limited to their use as acytochrome P450 system inhibitor. In other embodiments, an agent forinducing the cytochrome P450 system may also be used, including but notlimited to a rifamycin including rifabutin, rifampin and rifapentine, ananti-convulsant including carbamazepine, phenobarbital and phenytoin, ananti-HIV agent including efavirenz and nevirapine, and an herbal agentincluding St. John's Wort. A cytochrome P450 inducer may be usefulbecause it may reduce system side effects from localized delivery of atherapeutic agent that is metabolized by the cytochrome P450 system. Insome embodiments, a cytochrome P450 inhibitor and a cytochrome P450inducer may be used in conjunction with a therapy agent. For example,the effect of a locally delivered therapy agent may be boosted by thelocalized delivery of a cytochrome P450 inhibitor while a cytochromeP450 inducer may be provided either systemically or from a differentlocalized site or a site downstream from the cytochrome P450 inhibitorto reduce side effects of the therapeutic agent. Although theembodiments described above refer to a first therapeutic agent and asecond agent for modifying pharmacological effect of the firsttherapeutic agent, in other embodiments of the invention, more than onetherapeutic agent and/or more than one modifying agent may be provided.Any one therapeutic agent may be affected none, one or multiplemodifying agents, and any given modifying agent may affect one or moretherapeutic agents.

For example, ritonavir, an HIV protease inhibitor known to be one of themost potent inhibitors of the metabolic enzyme cytochrome P450monooxygenase, may be used to improve the pharmacokinetics of a drug (ora pharmaceutically acceptable salt thereof) which is metabolized bycytochrome P450 monooxygenase comprising coadministering ritonavir or apharmaceutically acceptable salt thereof. When administered incombination, the two therapeutic agents can be formulated as separatecompositions which are administered at the same time or different times,or the two therapeutic agents can be administered as a singlecomposition. Drugs which are metabolized by cytochrome P450monooxygenase and which may benefit from coadministration with ritonavirinclude cyclosporine, FK-506, rapamycin, paclitaxel, taxol, taxotere andothers.

In one embodiment of the invention, a pro-drug and a reactant are loadedinto the porous layer of a medical device. The reactant is capable ofconverting the prodrug to its active form. By using a reactant/prodrugpairing, the effect of the active form of the prodrug may be at leastpartially localizable to the implantation site of the device. This mayreduce the systemic side effects of a therapeutic agent. Areactant/prodrug pairing may also provide therapeutic activity with animplant that is otherwise not achievable due to the short half-life ofan active drug. In other embodiments, one or more reactants foundsystemically or locally at the implantation site are used to convert theprodrug into active form. Such reactants may include systemicallyavailable or localized enzymes.

In another embodiment, multiple therapeutic agents may be introducedinto a porous matrix composed of a plurality of porous layer 23. Asdescribed previously, the plurality of porous layers may vary in atomiccomposition, as well as in pore size and density. Compositionalvariations may allow for preferential binding to occur between thetherapeutic agent and the coating, changing the elution kinetics of theagent. Pore size and density will also affect the transport kinetics oftherapeutics from and across each layer. The use of a plurality ofporous layers may thus allow for controlling elution kinetics ofmultiple therapeutic agents.

In a further embodiment, live cells may be encapsulated within lumen 26of device 20. In one such embodiment, the entire device may be madeporous (such that the internal lumen and the exterior of the device areseparated by a porous layer). Live cells (such a pancreatic islet cells)can be encapsulated within the internal lumen, and the porosity of thelayer adjusted to allow transport of selected molecules (such as oxygen,glucose; as well as therapeutic cellular products, such as insulin,interferon), while preventing access of antibodies and other immunesystem agents that may otherwise attack or compromise the encapsulatedcells.

F. Loading of Therapeutic Agents Into a Porous Layer

A major challenge for using nanoporous coatings is to identify effectivemethods for loading therapeutic agents in a manner that carefullycontrols dosage, drug stability, drug mass, biocompatibility, releasekinetics, and overall device efficacy. One limitation that must beovercome is that coatings contain trapped air that can impede loadingwith drug loading solvents. This limitation can be overcome usingwetting processes as well as vacuum and/or pressure loading techniquesduring, following, and preceding introduction of the solvent containingthe therapeutic agent. One may also replace the gas within the coatingprior to the loading process with one that has high solubility in theloading solvent thus facilitating gas removal by diffusion processesand/or use solvents that have high solubility with air. For example, onemay use nitrogen or CO₂ gas that have higher solubilities than air inmany hydrophobic and hydrophic solvents compatible with loadingtherapeutic agents. One may also use the vapor or gas phase of theloading solvent in question in a “prewetting” step to greatly improvefilling of the nanopores within the PES with the loading solution.

Solvents used in the loading process must also have appropriateviscosities and wetting properties to allow their penetration deep intothe nanoporous coating, but also appropriate vapor pressures to enableeffective elimination of solvents after loading to ensurebiocompatibility, drug stability, rewetting with body fluids, and/orappropriate elution of the therapeutic agent. Several unique methodshave been identified that overcome these limitations.

One method is to simply dip the coated biomedical device into thesolvent containing the therapeutic agent but using solvents withappropriate solubility properties, vapor pressures, viscosity, andwetting properties to achieve appropriate loading of the coating. Oneembodiment would be to use ethanol for loading rapamycin or rapamycinanalog. Another embodiment is to use graded concentrations of ethanol,other solvents, or co-solvents that have different solubility propertiesfor the therapeutic agent to provide a wide range of concentrations forloading. Following loading, the biomedical device can then be subjectedto controlled washes or other specialized processing steps (see below)and subsequently air dried or dried under controlled vacuum for storageprior to subsequent manufacturing processes including sterilization, andpackaging. This method is most applicable to thin coatings (e.g. <1micron) but may also be used for depositing therapeutic agentsselectively on and within the upper layers of thicker coatings (>1micron).

Another method that may be desirable for loading thicker coatingsincludes performing loadings under controlled vacuum (subatmospheric)pressures. This includes use of both constant vacuum and with stepped orramped changes. In some embodiments of vacuum loading, it is beneficialto optimize vacuum pressures relative to solvent vapor pressures. Forexample, one can load rapamycin in ethanol, acetone, methanol, benzylalcohol, DMSO or other solvent with high rapamycin solubility undervacuum pressures that just exceed the vapor pressure of the solvent inquestion. Following loading for varying times from 1 minute to 30 daysor more depending on the coating thickness, the solvent can be removedby air drying or drying under vacuum pressures exceeding the vaporpressure of the solvent in question.

In another embodiment, the coating is placed in a subatmosphericpressure below the vapor pressure of the loading solvent to induceexchange of trapped air with the vapor phase of the loading solvent. Onethen can then introduce the PES device into the loading solutioncontaining the therapeutic agent at either subatmospheric, ambient, orsupraatmospheric pressure to optimize loading of the solvent containingthe therapeutic agent(s).

For example, in the case of ethanol, vacuum loading is typically done at60 torr or a pressure that exceeds the vapor pressure of 100% ethanolthat is approximately 45-50 torr at room temperature. Ideally, thevacuum pressure used will be 0.1 to 5 torr greater than the vaporpressure of the loading solvent (or solvents) under the conditions ofthe loading to prevent excessive or rapid loss of solvent during theloading process. However, in some embodiments, one may deliberatelycycle below and above the vapor pressure to facilitate removal oftrapped gas, and effective replacement with solvent containing thetherapeutic agent. The cycle times will typically be for periods rangingfrom 1-5 seconds in some applications, 5 seconds to 1 minute, 1 minuteto 10 minutes, or 10 minutes to several hours depending on the solvents,vapor pressures, agent being loaded, temperature, and other loadingconditions. Following loading, the samples are then subjected toprocedures to control the amount of surface deposition of therapeuticagent (see below), and either air dried or dried under vacuum pressureslower than the vapor pressure of water, and/or increased temperature toensure effective elimination of the solvent. One may also perform theloading process at reduced temperature to lower the solvent vaporpressure, thus allowing use of lower vacuum pressures to facilitate moreeffective removal of air and replacement with the loading solution. Thatis, one can reduce the loading temperature to just above the freezingpoint of the solvent to enable use of the lowest vacuum pressurepossible.

One specific embodiment of the preceding methods is to place the PESdevice in a vacuum chamber with a container of 100% ethanol, reduce thepressure in the chamber to a value generally below the vapor pressure ofethanol (e.g. <44 torr at 20° C.), close off the chamber, then allowexchange of ethanol vapor with air in the PES coating for a periodranging from about 1 minute to about several days or more, depending onthe PES coating thickness. The PES device is then introduced into asolution of 100% ethanol containing a therapeutic agent, such asrapamycin (sirolimus), at either subatmospheric, ambient, orsupraatmospheric pressure. In the case of non-ambient pressure loading,the preceding method may be performed using equipment that allows remotecontrol introduction of the PES device into the loading solution, asshown in FIGS. 9A and 9B. In another embodiment, the vacuum chamber isbrought to ambient pressure and the PES device is introduced manuallyinto the loading solvent containing the therapeutic agent and to thenproceed with subsequent loading processes as described elsewhere in thisapplication.

An additional method which is a modification of the preceding is to loadin one solvent as described, and to then remove the device and place ina second solvent with lower solubility for the therapeutic agent (withor without vacuum) thereby promoting selective precipitation of thetherapeutic agent both on and within the nanoporous coating. This methodhas the unique advantage of providing a “loading gain factor”—that isdeposition of a greater dosage of therapeutic agent than calculatedbased on the free volume within the coating times the concentration ofthe therapeutic agent.

One embodiment of this method is to load rapamycin within 100% ethanolat its maximum solubility of approximately 90 mg/ml and 50-60 torrpressure, to remove the device from the ethanol loading solution, and toimmediately place it in a solvent that has much lower rapamycinsolubility (e.g. 20% ethanol or physiological saline) with or withoutvacuum. The net result is precipitation of rapamycin within and on theinner surfaces of the nanoporous coating as well as at the interface ofthe solvents and on the surface of the coating. Examples of secondsolvents include 0.01%-100% ethanol (depending on desired dosage),water, phosphate buffered saline or other aqueous solution with orwithout rapamycin to provide controlled washing and deposition oftherapeutic agent on the surface of the biomedical device as well asprecipitation of the therapeutic agent within the coating.

An additional modification of the preceding methods is to precedeloading steps by replacing the gas within the nanoporous coating withone that has a higher solubility in the loading solvent than does air.For example, one embodiment for loading a hydrophilic drug like Gleevecwould be to carry out loading in an atmosphere of CO₂ which has a >20fold greater solubility in aqueous solutions as compared to air.Similarly, use of CO₂ would also facilitate removal of trapped gas andloading of hydrophobic drugs like rapamycin in solvents such as ethanol,methanol, and acetone.

In a preferred embodiment, the gas within the nanoporous coating mayalso be displaced or replaced with the vapor form of the loading solventor similar substance that is miscible with the loading solvent. Bycondensing the vapor form of the loading solvent into liquid form,mixing of the condensed vapor with the loading solvent can occur withoutconcern as to the solubility between the gaseous material and loadingsolvent. Condensation of the vapor form of the solvent may occurseparately by active or passive cooling of the loading environment, orduring the filling of the interstitial space by the solvent. The vaporform of the solvent may condense as it contacts the cooler liquid formof the loading solvent.

A further modification of the preceding methods is to subject the coatedbiomedical device to positive pressures during the loading process or tocycle between vacuum pressures and positive pressures. One embodimentwould be to perform and initial loading step for rapamycin in 100%ethanol at 60 torr, followed by application of a pressure greater thanatmospheric pressure to force loading solution (or precipitatingsolution) deeper into the nanoporous coating.

A further embodiment of the invention involves evacuating the air fromthe PES of the biomedical device by placing it in a vacuum for a periodof time prior to exposure to loading solvent containing the therapeuticagent. In this case the pressure in the PES is subatmospheric. One canthen immerse the device into loading solution within the vacuum systemand then bring the pressure to atmospheric or greater to enhance theloading process deep into the coating and pores due to the higherambient pressure than that present within the trapped gas or air in thepores. One embodiment of a loading device for this process isillustrated in FIGS. 9A and 9B.

Another loading method involves repeat loading and drying steps usingcombinations of the disclosed methods. For example, one embodimentincludes loading the PES with saturated or supersaturated solutions ofrapamycin or its analogs in 100% ethanol at 50-60 torr following by airdrying (or vacuum drying) between repeat loading steps. One can alsovary the loading times and/or temperature, as well as the washing orprocessing steps between loadings. Finally, one can alternate betweenvacuum loading and positive pressure loadings and use of solvents withhigh and low rapamycin solubilities.

It is advantageous, but not necessary, to use saturated or preferablysupersaturated loading solutions (e.g. made by adding a defined amountof additional solid therapeutic agent to a saturated solution) to avoidremoval of the therapeutic agent or agents deposited in previous loadingsteps. Use of these methods can result in increased loading of theagent. This increase can be several multiples of the theoretical drugloading achieved by traditional loading methods, as a calculated by thePES porous volume multiplied by the concentration of the therapeuticagent or agents in a saturated or supersaturated solution. Morespecifically, the drug concentration or drug loading of the PES porouslayer may be calculated by the following equation:drug concentration (ng/mm²)=A% void fraction/100×B μm layer thickness×C_(max) mM solution×D _(MW)/10³where A% is the average void fraction of the PES porous layer and B isthe average thickness of the PES porous layer in micrometers, C is themaximum concentration of the therapeutic agent in solution and D is themolecular weight of the therapeutic agent. In some embodiments of theinvention, a loading multiplier of at least about 5 times thetheoretical limit is achieved. Sometimes, at least about 10 times toabout 25 times the theoretical drug concentration is obtained. In stillother embodiments, a drug concentration of at least about 50 times orabout 100 times the theoretical limit is achieved by the methodsdescribed herein. For example, by using ethanol vapor exchange followedby repeated load-dry steps (with alternating vacuum levels)substantially higher levels of rapamycin concentrations can be achievedin a porous stent. In still other embodiments, crystalline rapamycin maybe deposited into the porous zone or formed in the porous zone,providing a concentration of at least about 1000 times to about 2000times or higher than the theoretical limit of rapamycin as calculated bythe above equation.

An additional challenge for loading therapeutic agents using solvents isselective removal of solvents and/or residual materials other than thetherapeutic agent upon completion of loading. In one embodiment of thecurrent invention, this process is accomplished by one or more offollowing procedures including but not limited to air drying at ambientpressure, drying at subatmospheric pressure, increasing the temperatureof the system, use of chemical desiccants selective for the solvents inquestion, and exposure to inert gases that can promote drying orneutralization of residual materials and solvents.

The preceding methods are not intended to be exhaustive but ratherillustrate just a few specific examples of the general loadingprinciples that can be employed to facilitate the loading and processingsteps for deposition of therapeutic agents within nanoporous coatings ofmany types and varieties.

An additional consideration in loading and processing nanoporouscoatings for controlled delivery of therapeutic agents involves steps tocontrol the surface and subsurface deposition of therapeutic agent.Processing steps may include batch washing in solvents with knownsolubilities for the therapeutic agent. Indeed one can calculate theexact volume of “wash” solvent to use to remove a precise amount oftherapeutic agent from the biomedical device (i.e. this is a function ofthe solubility, total payload of therapeutic agent deposited during theloading steps), and volume of the batch washing solutions). For example,one may employ a solvent with very low solubility for the therapeuticagent to minimize removal of surface agent if one wishes to optimize thetotal payload of therapeutic agent. However, in other cases, one maywish to reduce the “burst” release of therapeutic agent on the surface,and/or load a second therapeutic agent on the surface of the coating byhighly controlled washing with a solvent that selectively removes somesurface material thus allowing for more controlled surface deposition ofadditional therapeutic agents. For example, this may include use ofloading solvents for additional therapeutic agents that are relativelyinsoluble in the first loading solvent or which have a viscosityinconsistent with deep loading.

Additional methods for controlled deposition of therapeutic agents onthe surface of the nanoporous coating include batch processing withcontrolled air streams (including with high velocity air or othergases), and/or controlled mechanical wiping techniques.

The preceding loading and processing methods may be done at point ofmanufacture or at the site of use of the device. In some cases this mayrequire specialized equipment including but not limited to vacuum andpressure loading and washing devices. Referring back to FIGS. 9A and 9B,one embodiment of a loading device includes remote controlled initiationof solvent loading while the device is under vacuum. The loading devicecomprises a vacuum chamber 28 attached to a vacuum pump 30, a mechanicalor magnetic trigger 32, a reagent housing 34 attached to a hinge 36 andreagent tubing 38. The vacuum pump 30 is preferably a vacuum pump thatis able to remove air from the vacuum chamber and one or moreprogrammable elution stents place in the chamber 28. When the magnetictrigger 32 is released, the reagent housing 34 is able to swing down andallow the therapeutic agent 40 to flow through the reagent tubing 38until sufficient loading of reagent is reached. In another embodiment,the mechanical or magnetic trigger 32 controls a reagent pump thatprovides flow of therapeutic reagent onto the PES. The PES coatedbiomedical device may be secured within its container with a simplebatch loading device customized based on the properties of the device inquestion. For example, in the case of stents, they are held on a comblike device consisting of multiple “teeth” made of an inert materialinserted into the lumen of the stents and held such that adjacent stentsare separated to allow flow of loading solvent. One skilled in the artcan provide other configurations, depending on the particular device,therapeutic agent and other factors.

FIG. 10 depicts one example of the cumulative kinetics and elution rateof a hydrophilic therapeutic substance loaded into a PES. A two-micronthick nanoporous PES on a silicon wafer was loaded with a hydrophilicsubstance (4400 dalton FITC-dextran) under vacuum conditions for 72 hrs.FITC-dextran was employed for ease of quantitation but mimics release ofhydrophilic drugs and other substances. The FITC-dextran loaded PESdevices were washed 3 times in phosphate buffered saline (PBS) andplaced into 2.0 ml vial for elution. A sample volume was removed dailyfor measurement of FITC-dextran on a fluorometer (EX 485 nm); an equalvolume of PBS was re-added to the vial to maintain a volume of 2.0 ml.Arbitrary Cumulative FITC-dextran release values (left y-axis, bluecircles) and Elution Rate values (right y-axis, red triangles) wereplotted against time (x-axis, days). The PES continued to releaseFITC-dextran for at least 30 days.

FIG. 11 illustrates the changes in cumulative elution kinetics of atherapeutic substance with changes in porosity of a PES. Two micronthick nanoporous PES of porosity 1 and porosity 2 on a silicon waferwere loaded with FITC-dextran (a hydrophobic reagent, 4400 M.W)identically to that described in FIG. 10. The relative porosity ofsample “porosity 1” (upper curve) was greater than the relative porosityof sample “porosity 2” (lower curve). Increasing the porosity of the PESalters the relative amount of FITC-dextran loaded and released overtime. It should be noted that although results shown in FIG. 11 and thefollowing figures describe hydrophilic and hydrophobic drugs andchemical reagents, the storage and release properties illustrated applyto any therapeutic substance.

FIGS. 12A and 12B depict the changes to the cumulative elution kineticsof a reagent in the PES by changing the solvent. Two micron nanoporousPESs were loaded with rapamycin (also known as sirolimus, a hydrophobictherapeutic drug or reagent) dissolved in “solvent 1” (open boxes) and“solvent 2” (closed boxes). The PESs were loaded under vacuum conditionsfor 72 hrs. FIG. 12A represents the total payload in the PES by elutingdirectly in 2.0 ml of 1-octanol and determining rapamycin concentrationby spectrophotometry (absorbance wavelength of 279 nm). FIG. 12Brepresents cumulative elution kinetics of over 7 days by eluting into aPBS/1-octanol phase separation (a standard in the industry fordetermining elution rates of a hydrophobic drug).

FIG. 13 depicts changes in the payload of a reagent in a PES by changingthe load time. One micron thick nanoporous PESs were loaded withrapamycin (also known as sirolimus, a hydrophobic therapeutic reagent)under vacuum conditions for 24 and 72 hrs.

Referring to FIG. 14, a loaded reagent can be selectively removed fromthe PES by washing the device in various percentages of the originalsolvent. One micron thick nanoporous PESs were loaded with rapamycinunder vacuum pressure for 72 hrs. The PESs were then exposed to “percent1” (closed boxes) and “percent 2” (open boxes) of the original solventused to dissolve rapamycin and load the PES for 30 minutes, since thesolubility of rapamycin decreases with decreasing percentages ofrapamycin.

FIG. 15 illustrates how changes to the composition and loadingconditions for the PES alters reagent payload. One micron thicknanoporous PESs were loaded with repeat vacuum loading, drying, andwashing steps with rapamycin and payload determinations made asdescribed in FIG. 12. Results demonstrate the capacity to alter drugloading payloads with a combination of changes in PES and loadingmethods.

G. Other Effects of Nanoporous Layers

As mentioned previously, some embodiments of the invention relate tomethods of treatment using a porous coating that do not require atherapy-eluting component, such as tissue ingrowth or removal of variousagents through adsorption or absorption. Other non-therapy eluting usesfor porous stents are also contemplated within the scope of theinvention. For example, the inventors have discovered that the use of astent with a porous coating alone may have an effect on reducingstenosis or cellular proliferation in a vascular lumen. In one studyperformed by the inventors, a commercially available base metal stent(VISION® stent by Guidant, Inc., IN) was compared to the same stentcoated with a dealloyed porous coating of the disclosed invention toevaluate vessel stenosis over a 90-day period. Referring to FIG. 17, theresults of the study showed that the control base metal stents exhibiteda lumen stenosis of about 42% while the treated stents exhibited only alumen stenosis of about 25%. The study was performed in Yucatanminiswine pigs of ages 12 to 16 weeks and weighing 25 to 45 kilograms.Anesthesia was induced in each pig. A 7F catheter was inserted and thecoronary anatomy was visualized. A stent diameter was selected basedupon the visual estimate of the target vessel diameter to achieve about10 to 20% oversizing. Each subject received up to three stents in theLeft Anterior Descending Artery, Left Circumflex Artery or RightCoronary Artery, depending on the suitability of the coronary anatomy.The subjects were treated with clopidogrel for 28 days post-operativelyand aspirin throughout the study period. At the end of the study period,the subject was anesthetized and recatheterized with a 7F catheter andcoronary angiography was performed again. The subject was theneuthanized and the heart was removed for histopathological andquantitative morphometric analysis.

The reduced stenosis by the porous stent may be due to a number ofetiologies, including improved biocompatibility and tissue healing. Themere presence of a bare metal stent that lacks pores or configuredsurface structures in a vascular lumen may result in slippage, friction,fragmentation of cell-matrix-stent adhesions, and chronic irritation tothe tissue surrounding the bare metal stent. These effects may beworsened by the repetitive mechanical deformation of the blood vesselduring cardiac contraction and relaxation. Such effects and interactionsmay be reduced with stents comprising a porous coating. Studies by theinventors have shown that endothelial cells and smooth muscle cells haveimproved adhesion to porous coatings compared to bare metal surfaces. Aporous coating may provide increased adhesion of cells and extracellularmatrix components to the stent as compared to a bare metal stent, whichin turn promotes healing and/or reducing chronicirritation/inflammation. A porous coated stent may also improve theanchoring of the stent in the vascular lumen, which reduces themechanical forces generated at the interface between the stent andsurrounding tissue. Reduction of mechanical force at the stent-tissueinterface may also result in neuro-hormonal and autocrine/paracrineeffects that alter the tissue response to stent implantation. A porousstent may be used alone or in combination with a therapy-elutingcomponent to further modulate these changes. In some embodiments, ananoporous stent adapted to provide increased adhesion of cells andextracellular matrix components to the stent as compared to a bare metalstent, which in turn promotes healing and/or reducing chronicirritation/inflammation may have a pore size of about 0.1 nm to about500 nm, preferably about 1 nm to about 500 nm, and more preferably about1 nm to about 50 nm. In another embodiment, the pore size is about 20 nmto about 200 nm. Although not wishing to be bound by this theory, it isbelieved that in the embodiments described above, the pore range isbelow that which is known to elicit adverse cellular responses includingactivation of platelets, or immune cells as described by Park et al.Biomaterials 22:2671, 2001 and Edelman et al. Circulation 103 (3): 429.

An alternative or complementary mechanism that may be affect stenosisrates with porous stents is the elution or leaching of metals containedin the dealloyed coating. The metals used in the porous coating may beaffecting endothelial and smooth muscle cells, or may be alteringinflammatory or immunological pathways. This elution of metal may alsobe enhanced by the increased surface area of the dealloyed coatingcompared to a bare metal surface. These metals may include those used asstructural components in the porous matrix, as well as remnants of thoseused as a sacrificial material to form the pores or impurities from themanufacturing process. In one example, studies have demonstrated thatbiodegradable magnesium stents may be associated with significantbenefits in maintaining lumen diameter. Heublein et al., Biocorrosion ofMagnesium Alloys: A New Principle in Cardiovascular implant technology,89 Heart 651 (2003) and Di Mario et al., Drug-Eluting BioabsorbableMagnesium Stent 17 J. Interven. Cardiol. 391 (2004). The magnesium, inthe form of magnesium oxide (a solid, insoluble base), may also behydrolyzing in vivo and raising the local pH at the vascular lesion,which in turn may suppress cellular proliferation. Local alteration ofpH may also be achieved using other solid bases including barium oxideand calcium oxide. Magnesium may be reacting with anions, such aschloride ions present from the dissociation of sodium chloride ions inthe bloodstream. The magnesium may be reacting with and reducing theconcentrations of these anions that may act as biologically activeproliferative agents. Magnesium acts as a cation in aqueous solutions,which suggests that other cations may exhibit a similar effect, such asBe, Ca, Sr, Ba, Ra, Li, Na, K, Rb, Cs, and Fr. Other metals that may beused with the invention to affect vascular stenosis include cobalt,chromium, silver, gold, titanium, zinc, aluminum, manganese, tantalum,vanadium, and platinum.

H. Materials and Methods for Producing Devices With Nanoporous Features

In one embodiment of the invention, a vascular stent with a porouscoating is provided for insertion into a vascular lumen to resistvascular stenosis. The stent may comprise a material such as magnesium,cobalt-chromium, L605 or other cobalt-chromium alloy, 316L stainlesssteel, silver, gold, titanium, nickel, tantalum, vanadium, platinum,tungsten, nitinol, or alloys/combination thereof. The stent may have adiameter in the range of about 2.0 mm to about 15 mm, preferably about2.5 mm to about 5 mm and more preferably about 2.5 mm to about 3.5 mm.The length of the stent may range from about 5 mm to about 50 mm,preferably about 8 mm to about 40 mm and more preferably about 8 mm toabout 32 mm. Prior to deposition of the porous coating, the stent may beprocessed, cleaned or pretreated using ultrasonic methods and substancessuch as ethanol, acetone, TCA or TCE, inorganic bases such as sodiumhydroxide, ammonium hydroxide, potassium hydroxide; or inorganic acids,such as hydrochloric acid, hydrofluoric acid, sulfuric acid, nitricacid, phosphoric acid

In one embodiment, to deposit the porous coating, the stent undergoes DCbacksputter at about 15 milli-torr pressure of Ar+H₂ and biased to about1000 V for about 20 minutes. Pressure range for backsputter can be from2 milli-torr to 100 milli-torr, but preferably between 10 to 20milli-torr. Biasing can be DC in the range of 100 V to 2000 V,preferably in the range of 800 V to 1200 V. Alternatively, RFbacksputtering can also be used, in which case the bias of the stentwill be in the range of 100 V to 500 V. Back sputter times can be from 1minute to 120 minutes, but preferably between 10 minutes and 30 minutes.The porous coating may be deposited using a sputter process in apressure range range of 1-20 milli-torr Ar, preferably 2-15 milli-torrAr and more preferably 2 milli-torr Ar, and at a wattage of about 100 Wto about 1000 W, preferably about 200 W to about 500 W and morepreferably about 225W to about 300W or 400W, depending on the material.The sputter material may comprise chromium, L605, magnesium, aluminum,silver, copper, gold, vanadium, platinum, tungsten, titanium, aluminumoxide, silicon carbide, silicon dioxide, or silicon nitride. Thesputtering time may range from about 5 minutes to about 60 minutes,preferably about 6 minutes to about 30 minutes or even 60 minutes. Theremay or may not be a pre-sputtering conditioning period in the range ofabout 1 minute to about 5 minutes. In one embodiment, the pores of thestent range in size from about 10 nm to about 500 nm, preferably about15 nm to about 300 nm and more preferably about 20 nm to about 200 nm.After deposition, the stent may be treated with 1% HNO3 at roomtemperature, and subsequently annealed at 600 C for 10 minutes invacuum. The concentration of the dealloying solution may vary from 0.1%to 65% HNO3. The temperature of the dealloy solution may range from −5Celsius to 95 Celsius, but will preferably be in the range of 0 Celsiusto 70 Celsius. Alternatively, other acids or bases (organic orinorganic) may also be used to de-alloy the sputter deposited material.These reagents include sodium hydroxide, potassium hydroxide, ammoniumhydroxide, phosphoric acid, oxalic acid, hydrochloric acid, hydrofluoricacid, sulfuric acid. Annealing temperatures may vary from 200 C to 1200C, but will preferably be in the range of 500 C to 800 C. Annealingambient may be vacuum or a low pressure gas, such as Ar, Ne, N2, O2, H2,Xe, or combination thereof. The pressure of the gas during anneal may bein the range of 1 milli-torr to 100 milli-torr, but will preferably bein the range of 5 to 20 milli-torr. The porous coating may have aninterpore spacing between 1 and 20 times the size of the pores,preferably about 1 to 10 times the size of the pores and more preferablyabout 1 to 5 times the size of the pores. After processing or cleaning,the stent may be dried using N2 or other gases. The stent may or may nothave a therapy-eluting component. The therapy-eluting component, if any,may be integral with the porous coating. The porous coating need not becompletely filled with therapy-eluting component to its outer surface.By providing at least a portion of the porous coating with open pores,the porous coating may be adapted to reduce surrounding cellularproliferation and/or vascular stenosis.

The performance of these and other non-eluting features of theinvention, either alone or in combination with other eluting andnon-eluting characteristics of the invention may be determined oroptimized with routine experimentation by those of ordinary skill in theart. Stent characteristics related to porosity, directionality and/orconfiguration of the pores, material composition, method of delivery,self-expandability, balloon expandability, strut arrangement, length,thickness and diameter may be manipulated and still be contemplatedwithin the scope of the invention. Although dealloyed porous stents aredisclosed as non-limiting examples of the invention, other types ofporous stents or medical devices and non-porous stents that exhibitstenosis resistant properties are also contemplated.

In addition to coronary stents, other embodiments of the inventioncontemplate the use of dealloyed and/or porous coatings with othermedical devices, including but not limited to peripheral stents, biliarystents, cerebrovascular stents, vascular grafts, orthopedic fixationdevices such as plates and screws, implantable pacing leads and sensors,pacemaker and defibrillator housings, and others.

Although localized drug-eluting technologies such as drug eluting stentshave been used to provide greater tissue concentrations of therapeuticagent compared to systemic administration of a therapeutic agent, thefeatures of a dealloyed nanoporous stent may allow even higher tissueconcentrations of therapeutic agent than those provided by existingtechnologies. In one embodiment, the use of rapamycin with a dealloyednanoporous stent is capable of achieving tissue concentrations from 0.01to 2 ng/mg tissue, or about 2 ng/mg of tissue to more than about 2000ng/mg of tissue, based upon 7-day in-vivo values. In other embodiments,a dealloyed nanoporous stent is capable of achieving rapamycin tissueconcentrations from about 5 ng/mg of tissue to more than about 1000ng/mg of tissue, based upon 7-day in-vivo values, and in some instances,is capable of achieving rapamycin tissue concentrations from about 3ng/mg of tissue to about 100 ng/mg of tissue, based upon 7-day in-vivovalues, and in other instances is can achieve rapamycin tissueconcentrations from about 2 ng/mg of tissue to about 500 ng/mg oftissue, based upon 7-day in-vivo values. In still another embodiment, adealloyed nanoporous stent is prepared and loaded to achieve a rapamycintissue concentration from about 175 ng/mg of tissue to more than about500 ng/mg of tissue, based upon 7-day in-vivo values. The dealloyingprocess can provide the ability to control the localized delivery of atherapeutic agent using a morphologically scaleable technology.

1. EXAMPLE A

In one specific example, a coronary stent is co-sputtered with L605 (3.1A/s) and magnesium (9.7A/s) in 2×10-3 torr Argon, resulting in an alloycoating that is approximately 30% by weight of magnesium. The stent isdealloyed using a 1% HNO₃ at about 1° Celsius for about 5 minutes,followed by an anneal at about 600° Celsius for 10 minutes at about 10⁻⁵torr vacuum with a ramp rate of about 200° Celsius/minute. This processproduces a dealloyed layer as depicted in the scanning electronmicrograph in FIG. 18. The resulting porous zone is approximately 3% byweight of magnesium and has a range of pore sizes from about 1 nm toabout 25 nm.

In a further embodiment, the stent may be loaded with rapamycin using aprocedure whereby the stent is washed using absolute ethanol in a gentlyagitation of about 40 rpm for about 1 hour. The stent is then placed ina vacuum chamber along with a 7″×5″ reservoir of about 100 mL ofabsolute ethanol. The vacuum pump is set to a setting of about 1 torrand run for about 15 minutes. The chamber is then sealed, the pump isstopped, and the ethanol vapor from the reservoir is allowed to fill thechamber for 30 minutes. The chamber is vented to atmospheric pressureover about 5 minutes and then opened so that about 30 mL of absoluteethanol is applied to a container holding the stent and the ethanolreservoir is refilled. The vacuum pump is set for about 60 torr and runfor about 3 hours, then stopped and the chamber is slowly vented toatmospheric pressure over about 5 minutes. The stent is removed from thevacuum chamber and sprayed with compressed air to remove the excessethanol and placed in another vacuum chamber to air dry for 15 minutes.The vacuum pump is set to about 1 torr and run for 20 minutes to dry theethanol from the stent, followed by stopping the pump and venting thechamber to atmospheric pressure over about 2 minutes. This step is thenrepeated, at least one and preferably two or more times before the stentis removed from the drying vacuum chamber. The stent is placed inanother vacuum chamber with a reservoir of about 100 mL absolute ethanoland the vacuum pump is run for about 15 minutes at about 1 torr beforestopping the pump and allowing ethanol vapor to fill the vacuum chamberfor about 2 hours before venting the chamber to atmospheric pressureover about 5 minutes. About 10 mg of dry rapamycin power is thensprinkled into a container and about 10 mL of a 90 mg/mL rapamycinloading solution in absolute ethanol is provided to the dry rapamycin inthe container and the stent is submerged into the loading solution. Thisstep is to ensure supersaturation of the loading solvent with rapamycin.The container with the stent and loading solution is placed in a vacuumchamber with another ethanol reservoir and the vacuum pump is run forabout 3 hours at about 60 torr before stopping the pump and venting thechamber to atmospheric pressure over about 5 minutes. The stent isremoved from the container and sprayed with compressed air to removeexcess loading solution and then placed in another vacuum chamber to airdry for about 15 minutes. The vacuum pump is run for about 20 minutes atabout 1 torr to dry the ethanol from the stent and then the pump isstopped and the chamber is vented to atmospheric pressure over about 2minutes. The vacuum drying is repeated at least once and at leastpreferably twice more before removing the stent from the drying vacuumchamber. The loading procedure then repeated at least once more andpreferably two or three times or more but without the dry rapamycinpowder before undergoing ultra high vacuum (UHV) drying to removeresidual solvent from the stent. This procedure typically results in aninitial stent payload of about 80-100 micrograms of rapamycin on a 12 mm(length) by 3.5 mm stent. Placed in an in vivo porcine coronary arterystent model, the stent provides a 7 day tissue concentration of about1.00 ng/mg of tissue as measured by tandem MS/MS HPLC.

2. EXAMPLE B

In another specific example, a coronary stent is co-sputtered with L605(1.5 A/s) and magnesium (12 A/s) in 2×10⁻³ torr Argon for a resultingalloy coating that is approximately 80% by weight of magnesium. Thestent is dealloyed using a 1% HN03 at about 1° Celsius for about 5minutes, followed by an anneal at about 600° Celsius for 10 minutes atabout 10⁻⁵ torr vacuum with a ramp rate of about 200° Celsius/minute.This process produces a dealloyed layer as depicted in the scanningelectron micrograph in FIG. 19. The resulting porous zone isapproximately 5% by weight of magnesium and has a range of pore sizesfrom about 10 nm to about 200 nm. In a further embodiment, this stent isloaded with rapamycin using the same procedure as disclosed in ExampleA, resulting in an initial payload of about 85 micrograms. Place in anin vivo porcine coronary artery stent model results in a 7 day tissueconcentration of about 0.80 ng/mg of tissue as measured by tandem MS/MSHPLC.

3. EXAMPLE C

In still another specific example, a coronary stent undergoes a lowerlayer sputter deposition with L605 (1.5 A/s) and magnesium (12 A/s) in2×10-3 torr Argon, and followed by an additional upper layerco-sputtering with L605 (3.1 A/s) and Mg (9.7 A/s) in 2×10-3 torr Argon,for a resulting alloy coating has a lower layer thickness of about 750nm and an upper layer with a thickness of about 75 nm. Optionally, oneor both sputtering steps may be repeated one or more times, in analternating or other desired order, to create a layered columnar porouszone. In one embodiment, shown in FIG. 20, an additional two highmagnesium content layers, with one lower magnesium content layer issputtered to produce a five layer porous stent surface. The stent isdealloyed using a 1% HNO₃ at about 1° Celsius for about 5 minutes,followed by an anneal at about 600° Celsius for 10 minutes at about 10⁻⁵torr vacuum with a ramp rate of about 200° Celsius/minute. The resultingporous zone has a range of pore sizes from about 1 nm to about 200 nm.

The resulting porous zone is approximately about 5% to about 10% byweight of magnesium and has a range of pore sizes from about 10 nm toabout 200 nm. In one further embodiment, this stent is loaded withrapamycin using the procedure disclosed in Example A, resulting in aninitial payload of about 90 micrograms. Place in an in vivo porcinecoronary artery stent model results in a 7 day tissue concentration ofabout 1.70 ng/mg of tissue as measured by tandem MS/MS HPLC.

4. EXAMPLE D

In still example, a coronary stent undergoes a lower layer sputterdeposition with L605 (3.1 A/s) and magnesium (9.7 A/s) in 2×10-3 torrArgon, for a resulting alloy coating with about 30% magnesium content byweight. The stent undergoes thermal dealloying by heating the porouszone with a heat source at about 600° Celsius for 10 minutes at about10⁻⁵ torr vacuum with a ramp rate of about 200° Celsius/minute. Theresulting porous zone is about 10-15% by weight of magnesium with a poresize range of about 1 nm to about 25 nm, but with occasional largerspaces up to about 500 nm or more, as depicted in FIGS. 21A and 21B.Although not wishing to be bound by the theory, it is hypothesized thatthe different macroscopic morphologies as illustrated in FIGS. 21A and21B may result from different intrinsic film strains prior to thethermal dealloy process. In one further embodiment, the stent is loadedwith rapamycin using an alternative loading procedure as described inExample A, but where the stent not sprayed with compressed air to removeexcess ethanol or loading solution except after the final drug loadingstep. For each loading step, however, after the rapamycin loadingsolution is provided, the container holding the stent is placed into a−20° C. environment with a vacuum chamber and the vacuum pump is run forabout 60 hours at about 20 torr. The pump is stopped and the chamber isvented to atmospheric pressure over about 5 minutes before the stent isremoved and dried with absorbent sheet material before insertion into adrying vacuum chamber to air dry for about 15 minutes. The pump in thedrying vacuum chamber is then run for about 20 minutes at about 1 torrto dry the ethanol from the stent and then the pump is stopped and thechamber is vented to atmospheric pressure over about 2 minutes. Thedrying step is then repeated at least once, and preferably at leasttwice before the stent is placed in a vacuum dessicator under a moderatevacuum of about 450 torr and brought to room temperature byequilibration to a 4° C. environment for about 5 to about 10 minutes,then a laboratory benchtop for about 10 to about 20 minutes. This stenthas a resulting payload of about 180 micrograms and a 7 day tissueconcentration of about 5.00 ng/mg of tissue as measured by tandem MS/MSHPLC in an in vivo porcine coronary artery stent model. In a secondalternative embodiment, the stent may be loaded using the alternativeloading procedure described above except that all the loading steps areconducted at a temperature of about −20° Celsius and the stent isthermally equilibrated during only during the dessication step of thelast loading cycle where the stent is placed in a vacuum dessicatorunder a moderate vacuum of about 450 torr and brought to roomtemperature by equilibration to a 4° C. environment for about 5 to about10 minutes, then room temperature for about 10 to about 20 minutes. Thisalternative procedure results in a stent with a payload of about 670micrograms and a 7 day tissue concentration of over about 900 ng/mg oftissue as measured by tandem MS/MS HPLC in an in vivo porcine coronaryartery stent model.

One of skill in the art will also understand that the various dealloyingand loading procedures may be varied using routine experimentation tomodify the delivery profile of the coronary stent. For example, theabove examples may be further altered by one with skill in the art toproduce further variations in pore morphologies by either rotating thestent or the deposition apparatus around the stent, altering the angleof incident of the deposition process, altering the rate of thedeposition or the temporal period at which material rate and/orcomposition of material is changed. Such changes can be used to alterthe intrinsic strain and grain structure of the deposited material.

To increase pore size, one would generally increase the amount ofsacrificial material within the as deposited coating. For example,increasing the deposition rate of magnesium relative to L605 willproduce a high magnesium pre-cursor material. When dealloyed, thismaterial would likely have bigger pores. Similarly, one could reduce theL605 deposition rate to produce a similar result.

While the ratio of magnesium to L605 may be a useful parameter to alterwhen manipulating pore morphology, the absolute values may also berelevant with respect to the net rate at which the material isdeposited. Typically, but not always, materials sputter deposited athigh rates tend to be more columnar than materials deposited at lowerrates, as the incoming material has less time relax into the idealdenser state.

Deposition rates may also be useful when heat dissipation becomes alimiting factor. In one particular example, if the deposition rates ofMg:L605 are increased to the point where sample heating becomes anissue, the strain introduced into the deposited film may cause spallingand delamination upon dealloying. Further, keeping the ratios of Mg:L605constant and altering total deposition rate may sometimes yield unusualmorphologies if heat is not dissipated in a rapid manner.

In some of the embodiments described previously where a more columnarpore structure is desired, the pressure in the chamber may be increasedduring the deposition process. This generally would lead to depositedmaterial having a more columnar structure. Consequently, the dealloyedmaterial would also reflect a similar structure.

The dealloying may also be manipulated to alter pore sizes. Generally,if one were to increase the dealloy time, more of the sacrificialmaterial will be removed and consequently the material would have biggerpores. However, in certain material systems (such as L605), the porestructure is typically defined a priori. For example, during thedeposition process magnesium may segregate preferentially to grainboundaries and/or into occlusions. These magnesium-rich areas, whendealloyed, become pores or voids. The form and distribution of thesemagnesium-rich spaces is typically dictated by the deposition conditionsdescribed above.

In another embodiment, by altering the thermal processing, by eitherpost chemical anneals and/or direct thermal dealloying, pore size mayalso be altered. Generally, the longer and/or hotter the thermalprocess, the more magnesium is driven off, resulting in larger pores.Various combinations of chemical and thermal processing, as well the usea reactive gas or reactive plasma previously mentioned, may also be usedto further alter pore size.

Furthermore, a lesser or greater amount of therapeutic agent may beloaded into the porous zone by varying the loading procedures disclosedabove. In some embodiments, the stent may be loaded with about 50micrograms to about 2,000 micrograms of therapeutic agent, preferablyabout 70 micrograms to about 1,000 micrograms of therapeutic agent, andmost preferably about 100 micrograms to about 800 micrograms oftherapeutic agent. The increased payload may be achieved by altering therapamycin concentration of the loading solution.

Although the specific examples disclosed above describe the applicationof an alloy coating onto an existing coronary stent to produce thedealloyed nanoporous zone, as mentioned previously, in other embodimentsthe alloy materials may be integrally formed with the stent rather thanco-sputtered. Also, although the specific examples provided aboveutilize rapamycin, other therapeutic agents, alone or in conjunctionwith other therapeutic agents, may be loaded onto a stent or medicaldevice through routine experimentation by one with ordinary skill in theart.

In one embodiment of the invention, a medical device comprising a porouszone further comprises a hydrophobic material deposited onto at least aportion of the porous surface of the porous zone. Because porous metalsystems are typically hydrophilic in nature and water has a very smallcontact angle with these materials, metallic pore structures tend to wetreadily. For example, a drop of water applied to a PES surface will bewicked up and spread out by capillary forces. This wetting may have anundesirable effect of increasing the solvation rate of therapeuticagents retained in these porous zones and may result in a more rapidrelease of drug from the porous zone than is desired. Although notwishing to be bound by the hypothesis, it is believed the presence of ahydrophobic material or coating on at least a portion of the PES willdelay the incursion of water into the PES and possibly retard therelease kinetics of the therapeutic agent or agents from the PES. Thehydrophobic materials that may be deposited include but are not limitedto fluorocarbons (e.g. PFE or PTFE), silicon nitride, silicon carbide,nickel nitride, chromium nitride, aluminum oxide, and aluminum nitride.The hydrophobic materials may be used as a final coat, and/or embeddedduring the pre-cursor deposition phase.

Alternatively, increased hydrophobic behavior may be achieved bysubjecting the dealloyed PES to an anneal process that would alter thechemical composition of at least a portion of the pore surface of thePES. One example of this would be nitridizing the surface under a DCplasma in the presence of nitrogen or ammonia. Similar processes, suchas RF plasma in the presence of CHF3, may also be used to synthesizehydrophobic material (such as PTFE) onto/into the PES.

In another embodiment of the invention, a nanoporous structure may beapplied or formed on at least a portion of a medical device to increasethe radio-opacity or echogenicity of the medical device underradiographic visualization, including but not limited to fluoroscopy, CTscanning, plain film X-ray, ultrasound and other visualizationmodalities. The radio-opacity of medical devices, especially of coronarystents during fluoroscopy, may be important in assisting physicians inoptimizing device placement and confirming device location during aninvasive procedure or during post-procedure follow-up. Although notwishing to be bound by such a hypothesis, it is believed that thenanoscale structure of the PES coating may enhance the radio-opacity ofan implantable device by increasing x-ray scattering. In particular, ananoporous zone comprising a directional pore structure or columnarfilaments may provide a surface configuration for increase x-rayscattering, resulting in reduced x-ray transmission and increasedopacity. For example, it has been observed during in-vivo proceduresthat an L605 PES nanoporous material, similar to that depicted in FIG.20, appears to be more radio-opaque than a stent coated with gold PES ofa similar thickness similar to that shown in FIGS. 7A and 7B. This is asurprising result given that gold has a higher atomic number (79) thantungsten (74), the heaviest component of L605.

As mentioned previously, the roughness of the porous surface may play arole in reducing the inflammatory response induced in the adjacentvascular tissue. Some studies, such as “Gold-Coated NIR Stents inPorcine Coronary Arteries” by Edelman ER et al, Circulation 2001 103:429-434, herein incorporated by reference in its entirety, havedemonstrated that smoothing the surface of a stent by heating it candecrease the Rt and the vivo porcine coronary artery thrombogenicity. In“Platelet interactions with titanium: modulation of platelet activity bysurface topography” by Park, J Y et al, Biomaterials 22 (2001)2671-2682, herein incorporated by reference in its entirety, the authorsdemonstrated that SEM may be used to calculate optical profilometricdata such as R_(a), average roughness, R_(q), root mean squaredroughness, R_(z), the average of the 10 greatest peak to valleyseparations within the sampling area, and R_(t), peak to valleydifferences. The data showed that platelet adhesion and activation wasgenerally proportional to Ra, Rq, Rz and Rt. A smaller Rt seems toresult in decreased platelet activation and adherence. Although notwishing to be bound by this hypothesis, we hypothesize that a dealloyedporous surface may reduce platelet adhesion and activation by providinga smoother outer surface with a lower Rt or other roughness measure. Ingeneral, Rt values less than about 3 microns have been shown to havereduced thrombogenic effect. As mentioned previously, we postulate thatembodiments of this invention having a pore size from about 0.1 nm toabout 500 nm has unique properties in promoting tissue healing, improvedcell adherence and anchoring, and may be provided alone or with areduced porous zone surface roughness to also decrease plateletactivation and adherence. A structure with these characteristics,through dealloying or other porosity means, may be beneficial inreducing the risks associated with implantation of medical devices,especially bare stents or drug eluting stents. That is, one can achievethe benefits of improved cell adhesion and healing without risksassociated with activation of platelets or inflammatory cells.

I. Nanoporous Bonding Layers

In addition, the porous layer may provide a means to better anchor thesematerials to the surface of the stent or other biomedical devicesthereby overcoming a major current limitation in these technologies ofseparation or delamination as illustrated in FIGS. 1 and 2. The risk ofdelamination of the polymer coating from the stent or other medicaldevice is reduced by the mechanical interfit which occurs as a result ofthe polymer flowing into the tortuous porous interface and thenpolymerizing or otherwise hardening in place. This results in a largenumber of independent interlocking points, distributed throughout theinterface between the polymer and the porous surface (i.e. rooting ofthe polymer to the metallic device).

The pore size and pore geometry may be optimized with each specificpolymer, taking into account the viscosity or flowability of the polymeror polymer precursors during the manufacturing process. Manufacturingconditions should be selected so that at least some polymer flows intothe pores to provide the interlocking interface following hardening. Thepore size may be larger (e.g., micropores) for the bonding function thanfor direct drug containment as disclosed elsewhere herein. In general, aselective dissolution or dealloying process is one method for producingtortuous, non-linear or angular pores in the surface of a stent ormedical device. Furthermore, the pores resulting from a dealloyingprocess can have an interconnecting relationship. Such pores can providea mechanical interfit between a bonding surface and an elution coatingthat traditional surface treatments such as acid and laser etching andmechanical roughening do not provide.

The enhanced bonding aspect of the present invention may additionallyinvolve the use of a tie layer between the outer polymer layer and thesurface of the medical device. For example, a porous stent may beprovided with a first layer of a first polymer or other bonding mediawhich has characteristics that produce a good mechanical interfit withthe porous surface. A second layer may thereafter be bonded to the firstlayer to produce the coated medical device. The second layer is thefunctional layer, such as a drug delivery layer. In this configuration,the second layer may be optimized for its drug delivery or otherfunction, without regard for whether it can bond effectively to thematerial or surface structure of the porous substrate.

The tie layer may comprise any of a variety of materials which can becaused to flow into the pores, and is bondable to the functional layer.Thermoplastic materials such various densities of polyethylene can beheated to a flowable state, applied to the porous layer and then cooledto provide the tie layer. Alternatively, the porous surface may beexposed to any of a variety of monomers or other polymer precursorswhich are allowed or caused to flow into the pores prior topolymerization.

The functional layer may thereafter be applied to the tie layer usingany of a variety of techniques such as dipping, spraying, condensationor others depending upon the nature of the functional layer.

Using a porous layer as a bonding interface may also allow bonding of agreater range of polymers and other coating materials with medicaldevices. One skilled in the art is no longer restricted to coatingmaterials with a particular bonding characteristic, as the porous layermay allow bonding of materials that would otherwise fail to bondadequately to a non-porous device surface. In one embodiment of theinvention, a medical device with a porous bonding surface is provided.The surface may have an average thickness of about 0.1 microns to about1000 microns, and preferably about 0.1 microns to about 10 microns. Theaverage pore size ranges from about 1 nanometer to about 100 microns,and preferably about 10 nanometers to about 5 microns. In otherembodiments, the average pore size is about 1 nm to about 50 nm. Theporosity of the bonding surface may range from about 1% to about 99%,typically about 25% to about 75% and preferably about 50% to about 70%.In other preferred embodiments, the porosity of the bonding surface isabout 40% to about 70%. In another embodiment of the invention, themedical device comprises a drug-eluting polymer coating bonded to thenanoporous bonding surface. In one embodiment of the invention, themedical device is a metallic coronary stent with porous metallic bondingsurface bonded with a paclitaxel or sirolimus slow-release polymercoating. One skilled in the art will understand that any of a variety ofother therapeutic agent-impregnated, slow-release polymer coatings maybe used. The porous bonding layer also may be nanoporous. In oneembodiment of the invention, the polymer material is applied to thesurface of the PES or other nanoporous coating wherein the polymersolvent is chosen based on its physical properties to control the extentof penetration (or wicking) of the polymeric composition into thenanopores. Physical properties to consider include but are not limitedto viscosity, wetting, vapor pressures, and drying times. One can alsovary the conditions for applying the polymer-solvent mixture to controlthe extent of polymer penetration into the nanoporous coating. Forexample, one can vary the spray distance, the initial polymer:solventratio, and spray velocity in such a manner to control the “wetness” orsolvent/polymer ratio at the instant it reaches the nanoporous coating.Generally, the wetter the mixture is at the instant of deposition, thegreater the penetration or wicking into the nanoporous structure. In anextreme example, conditions are varied such that the solvent:polymercomposition and application conditions are selected such that it isnearly completely “dried” at the time of deposition on the nanoporousdevice, such that there is virtually no penetration of thepolymeric:solvent mixture into the nanoporous coating. These fewexamples are by no means inclusive, and there are a wide range ofdifferent solvents, and application methods that can be varied tocontrol penetration into the nanoporous coating. Note that theseprinciples apply irrespective of the method used to generate thenanoporous coating and are applicable to any polymeric or other coatingmaterial.

In one embodiment of the invention, the medical device comprises ametallic coronary stent with one or more porous regions, a polymericprimer layer bonded to the porous regions, and a drug release layerbonded to the polymeric primer layer. For example, to improve polymeradherence, one may use a parylene C coat on a metallic stent prior toapplication of a polyethylene-co-vinyl acetate (PEVA) and poly n-butylmethacrylate (PBMA) drug bearing polymer coat. Other polymeric primerlayer materials that may be used include but are not limited to apolyfluoro copolymer, an ethylene vinyl alcohol copolymer, poly-lactideco-glycolide (PLGA) or other biodegradable polymers including but notlimited to poly lactic acid (PLA), or derivatives, or poly(butylmethacrylate). One skilled in the art will understand other drugreleasing materials may be used in addition to PEVA and PBMA.Additionally, a drug-free topcoat of PBMA, PLGA, or PLA may be used toalter drug delivery.

J. Nanoporous Layers With Polymer Topcoats

As mentioned previously, the porous zone may further comprise a topcoator other surface coating to further control the release kinetics of thetherapeutic agent(s) contained within the dealloyed porous zone.Typically, the topcoat or surface coating comprises a polymer.Optionally, a cross-linking agent may be included. An optional primerlayer can be applied between the dealloyed porous zone to improve theadhesion of the topcoat to the dealloyed porous zone. An optionalfinishing layer may also be applied over the topcoat layer and can beused for improving the biocompatibility of the underlying layer. Thefollowing is a more detailed description of suitable materials or agentsand methods useful in producing the topcoats or surface coatings of theinvention.

In one embodiment, the topcoat layer or layers are applied to a porouslayer already loaded with therapeutic agent, drug, or other substanceusing the methods described herein. The solvent used for dissolving andapplying the topcoat materials are chosen based on their wetting,solubility properties for the therapeutic material, drying time,viscosity, and other properties to control the amount of drug that mixeswithin the top coat, to regulate penetration of the top coat materialsinto the coating and to give desired release kinetics as well as topromote polymer anchoring to the nanoporous coating. In this manner, oneskilled in the art can create a wide range of end products with varyingelution properties, as well as enhanced adherence to the biomedicaldevice by virtue of rooting within the PES. The penetration of thepolymer-solvent material into the nanoporous layer may be characterizedby any of a variety of measures. In one embodiment, the penetration ofthe polymer-solvent material may be measured by the amount or percentageof the interstitial space in the nanoporous layer that is filled by thepolymer-solvent material, or by the depth of penetration across thenanoporous layer. The interstitial space may be filled by any amountfrom about 1% to about 100%. In other embodiments, to further increaserooting or anchoring of the topcoat or bonded polymer layer, theinterstitial space may be filled up to at least about 30% or about 60%.Similarly, when penetration of the polymer-solvent mixture is measuredas a depth of penetration of the porous layer, the percent ofpenetration may be anywhere from about 1% to about 100%. In otherembodiments, to further increase rooting or anchoring of the topcoat orbonded polymer layer, the interstitial space may be penetrated to adepth of at least about 30% or about 60%. In another embodiment of theinvention, it is recognized that the degree of penetration of thepolymer-solvent mixture may be affected by the average pore diameter ofthe nanoporous layer. In such embodiments, the degree of penetration maybe characterized as a ratio of the distance of penetration to theaverage pore diameter of the nanoporous layer. This ratio may rangeanywhere from about 0.1 to about 500 or more. In some embodiments, theratio is at least about 10, while in other embodiments, the ratio may beat least about 50 or about 100. One or measures of polymer-solventpenetration may be more appropriate, depending on the characteristics ofthe polymer-solvent material and/or the nanoporous layer. For example,if the filling of the nanoporous structure along the pore pathways bythe polymer-solvent mixture is incomplete, measures of penetration depthmay be more accurate than estimated measures of filling percentage. Inone embodiment, a top coat solvent with high solubility, low viscosity,slow drying/curing rates, and high wetting characteristics is used tocreate a final product with significant drug contained within the topcoat, but also significant top coat materials embedded within the porouscoating. Alternatively, one could use a top coat solvent with lowsolubility for the therapeutic agent, fast drying/curing time, and lowwetting properties to create a top coat that is largely devoid of drugand where there is relatively less polymer material embedded into theporous coating. This latter product would be expected to show delayedrelease kinetics. These are merely two examples of an infinite range ofpossibilities whereby selection of specific solvents, applicationmethods, therapeutic agents, and other related parameters can be varyingto create a final combination porous layer with top coats that displaydifferent elution rates and/or adherence properties.

In one embodiment of the invention, the polymer material is sprayed ontothe surface of the PES, the polymer material comprising therapeuticagent(s) and polymer solvent(s) chosen with specific propertiesincluding but not limited to viscosity, drug solubility, wetting, vaporpressures, and drying times to precisely control both mixing of drugwithin and on the nanoporous coating within the polymer coating, as wellas to control penetration of the polymer into the nanoporous coating toimprove rooting and anchoring. For example, if it is desired to haveextensive mixing of rapamycin with polymer and extensive penetration ofthe mixture into the nanoporous coating, one could use ethanol as thepolymer solvent of choice since it has an extremely high rapamycinsolubility (>90 mg/ml) but also low viscosity and a relatively longdrying time relative to other solvent choices such as acetone (bp=56.2vs 78.3 for ethanol). That is, use of acetone would result in reducedmixing of drug and polymer as well as reduced penetration of the mixtureof polymer and drug into the PES or nanoporous coating because of itslower rapamycin solubility and faster drying time. In anotherembodiment, one could use ethyl acetate as the polymer solvent ofchoice. This solvent has a boiling point (bp) approximately the same asethanol (77.1 C) but with a lower rapamycin solubility. As such, onecould achieve a topcoat that has excellent penetration and adherence tothe nanoporous coating, but much less drug within the coating itself.One can also vary the conditions for applying the polymer-solventmixture to control the extent of drug-polymer intermixing andpenetration into the nanoporous coating. For example, one can vary thespray distance (generally between about I mm and about 20 cm but morepreferably between about 0.5 cm and about 5 cm using a Sono-tekMicroMist Stent Coating System (Milton, N.Y.)), the initialpolymer:solvent ratio (between about 0.1 and about 100% but preferablybetween about 0.5 and about 3%), and spray velocity (generally betweenabout 0.001 and about 1.0 ml/min but preferably between about 0.010 andabout 0.075 ml/min) in such a manner to control the “wetness” orsolvent/polymer ratio at the instant it reaches the nanoporous coating.Generally, the wetter the mixture is at the moment of deposition orcontact with the nanoporous surface, the greater the mixing with drugwithin and on the nanoporous coating, which typically results in greaterpenetration of (or wicking into) the nanoporous structure. In an extremeexample, conditions are varied such that the solvent:polymer compositionand application conditions are selected such that it is nearlycompletely “dried” at the time of deposition on the nanoporous device,such that virtually no drug solvent mixing occurs, or penetration of thecoating into the nanoporous coating. These few examples are by no meansinclusive, and there are a wide range of different drug solvents, andapplication methods (i.e. spraying conditions, dipping methods, etc.)that can be varied to control drug-polymer mixing and penetration intothe nanoporous coating. Note that these principles apply irrespective ofthe method used to generate the nanoporous coating and are applicable toany drug, compound, or other therapeutic agent or combination thereof.Although not inclusive, additional solvents to consider for applicationof rapamycin are listed in Table 1 of Simamora et al Int J Pharmaceutics213: 25-29, 2001. Each solvent has distinct physical and solubilityproperties to allow selective control of drug-polymer mixing andpenetration into nanoporous coatings. Solvents include but are notlimited to the following solvents or solvent classes: ethanol, methanol,acetone, chloroform, ethyl acetate, THF, benzyl alcohol, ethyl lactate,polyethyethylene glycol, propylene dlycol, dlycerin triacetin, diacetin,acetyl triethyl citrate, ethyl lactate N-methyl-2-pyrrolidinone,buyrolactone, dimethyl isosorbide, tryethylene glycol dimethyl ether,ethoxy diglycol, glycerol, glycerol formal, dimethyl formamide, dimethylacetamide, dimethyl solfoxide, CHCL3, ketones, or alcohols.

The net consequences of these topcoat deposition methods are to alterdrug release kinetics, payload capacity, and adhesion to the biomedicaldevice. For example, in the case of promoting mixing, one can achievemore rapid onset of release because of the absence of a drug free topcoat. Alternatively, one may achieve slower release kinetics bydepositing a relatively drug free polymeric top coat without drug. Inaddition, one may vary the coating thickness and/or density to alter therelease kinetics of a therapeutic agent. For example, a thicker and/ordenser polymeric coating may be used to slow the release kinetics. Anadditional embodiment of the invention, is to include a drug, compound,or other therapeutic agent within the solvent:polymer mixture prior toapplication. In this manner, one can vary the drug concentration withinthe final polymeric topcoat and achieve differing release properties.Still another embodiment, is to perform polymeric top coat applicationsunder conditions described elsewhere in this application (e.g. use oflow vacuum, pressure, and temperature cycles, solvent prewetting steps,etc.) that facilitate removal of trapped gas from within nanoporouscoatings and improved penetration of polymer-drug mixtures. For example,the entire process can be done under vacuum at pressures just exceedingthe solvent vapor pressures/boiling points. The principle is that themore extensive the drug-polymer mixing and the deeper the penetration ofthis mixture, the slower the release kinetics and the more robust thepolymer adherence is to the biomedical device. Moreover, theseparameters can be carefully controlled by appropriate selection andmatching of solvents, drugs, nanoporous coating morphologicalcharacteristics, and application methods just to name a few of thecontrol variables possible to achieve the desired end product.

The polymer(s) useful for forming the coating should be ones that arebiocompatible and avoids irritation to body tissue. In one preferredembodiment, the polymers are biostable ones, such as polyurethanes,silicones, and polyesters. Other polymers which can be used include onesthat can be dissolved and cured or polymerized on the medical device. Inanother preferred embodiment, a bioerodable or biodegradable materialmay be used in the topcoat provide control of the release kinetics fromthe dealloyed porous zone that diminishes over time so that permanent orlong-term trapping of a therapeutic agent in the dealloyed porous zonemay be reduced while prolonging the initial release profile afterimplantation. Suitable polymers include polyolefins, polyisobutylene,ethylene-alphaolefin copolymers, acrylic polymers and copolymers, vinylhalide polymers and copolymers such as polyvinyl chloride, polyvinylethers such as polyvinyl methyl ether, polyvinylidene halides such aspolyvinylidene fluoride and polyvinylidene chloride, polyacrylonitrile,polyvinyl ketones, polyvinyl aromatics such as polystyrene, polyvinylesters such as polyvinyl acetate; copolymers of vinyl monomers,copolymers of vinyl monomers and olefins such as ethylene-methylmethacrylate copolymers, acrylonitrile-styrene copolymers, ABS resins,ethylene-vinyl acetate copolymers, polyamides such as Nylon 66 andpolycaprolactone, alkyd resins, polycarbonates, polyoxymethylenes,polyimides, polyethers, epoxy resins, polyurethanes, rayon-triacetate,cellulose, cellulose acetate, cellulose butyrate, cellulose acetatebutyrate, cellophane, cellulose nitrate, cellulose propionate, celluloseethers, carboxymethyl cellulose, collagens, chitins, polylactic acid,polyglycolic acid, and polylactic acid-polyethylene oxide copolymers.Other coating materials may include lactone-based copolyesters,polyanhydrides, polyaminoacids, polysaccharides, polyphosphazenes, poly(ether-ester) copolymers, and blends of such polymers, poly(ethylene)vinylacetate, poly(hydroxy)ethylmethylmethacrylate, polyvinalpyrrolidone; polytetrafluoroethylene, and cellulose esters.

More preferably for medical devices which undergo mechanical challenges,e.g. expansion and contraction, the polymers are selected fromelastomeric polymers such as silicones (e.g. polysiloxanes andsubstituted polysiloxanes), polyurethanes, thermoplastic elastomers,ethylene vinyl acetate copolymers, polyolefin elastomers, and EPDMrubbers. Because of the elastic nature of these polymers, the topcoatbetter adheres to the surface of the porous zone when the medical deviceis subjected to forces or stress.

Poly(ethylene-co-vinyl alcohol (EVAL) is one example of a polymer thatcan be included in the optional primer layer, the topcoat layer and thefinishing coat layer. EVAL has the general formula—[CH2-CH2]m-[CH2-CH(OH)]n-. EVAL is a product of hydrolysis ofethylene-vinyl acetate copolymers and may also be a terpolymer includingup to 5 molar % of units derived from styrene, propylene and othersuitable unsaturated monomers. A brand of copolymer of ethylene andvinyl alcohol distributed commercially under the trade name EVAL byAldrich Chemical Co. of Milwaukee, Wis., and manufactured by EVALCompany of America of Lisle, Ill., can be used.

Other suitable polymers can also be used for making the optional primerlayer, the topcoat layer and the finishing coat layer. Representativeexamples include poly(hydroxyvalerate), poly(L-lactic acid),polycaprolactone, poly(lactide-co-glycolide), poly(hydroxybutyrate),poly(hydroxybutyrate-co-valerate), polydioxanone, polyorthoesters,polyanhydride, poly(glycolic acid), poly(D,L-lactic acid), poly(glycolicacid-co-trimethylene carbonate), polyphosphoesters, polyphosphoesterurethanes, poly(amino acids), cyanoacrylates, poly(trimethylenecarbonate), poly(iminocarbonate), co-poly(ether-esters) (e.g. PEO/PLA),polyalkylene oxalates, polyphosphazenes, biomolecules (such as fibrin,fibrinogen, cellulose, starch, collagen and hyaluronic acid),polyurethanes, silicones, polyesters, polyolefins, polyisobutylene andethylene-alphaolefin copolymers, acrylic polymers and copolymers, vinylhalide polymers and copolymers (such as polyvinyl chloride),polyvinylidene halides (such as polyvinylidene fluoride andpolyvinylidene chloride), polyvinyl ethers (such as polyvinylmethyl-ether), polyacrylonitrile, polyvinyl ketones, polyvinyl aromatics(such as polystyrene), polyvinyl esters (such as polyvinyl acetate),copolymers of vinyl monomers with each other and olefins (such asethylene-methyl methacrylate copolymers, acrylonitrile-styrenecopolymers, ABS resins, and ethylene-vinyl acetate copolymers),polyamides (such as NYLON 66 and polycaprolactam), alkyd resins,polycarbonates, polyoxymethylenes, polyimides, polyethers, epoxy resins,polyurethanes, rayon, rayon-triacetate, cellulose, cellulose acetate,cellulose butyrate, cellulose acetate butyrate, cellulose nitrate,cellulose propionate, cellulose ethers, carboxymethyl cellulose,CELLOPHANE and mixtures thereof.

Poly(ethylene glycol) (PEG) is one example of a polymer that can beincluded in the topcoat layer and/or the finishing coat layer. PEG is abiologically compatible product having the formulaH—[O—CH2-CH2-O—H2-CH2]n-OH, and can have a molecular weight within arange of between about 1,000 and about 100,000 Daltons, for example,between 2,000 and 10,000 Daltons, such as 5,000 Daltons. The value ofthe integer “n” in the formula of PEG is about 56 for PEG havingmolecular weight of about 5,000.

Other suitable polymers can also be used to form in the topcoat layerand/or the finishing coat layer. Representative examples includeheparin, hyaluronic acid, and silk-elastin protein block-copolymer.Heparin comprises a mixture of sulfated polysaccharide chains based onD-glucosamine and D-glucoronic or L-iduronic acid. A brand of heparinknown under the trade name DURAFLO can be used. DURAFLO can be obtainedfrom Baxter Healthcare Corporation of Deerfield, Ill. Hyaluronic acid isa linear polysaccharide composed of disaccharide units ofN-acetylglucosamine and D-glucoronic acid. In hyaluronic acid, uronicacid and the aminosugar are linked by alternating β-1,4 and β-1,3glucosidic bonds. Silk-elastin protein block-copolymers combine therepeating blocks of amino acids thus providing the copolymer with the,mechanical strength characterizing silk and the flexibilitycharacterizing elastin. Silk-elastin block-copolymer can be obtainedfrom Protein Polymer Technologies, Inc. of San Diego, Calif.

Although the invention can be practiced by using a single type ofpolymer to form the topcoat layer, various combinations of polymers canbe employed.

According to an embodiment of the present invention, the polymericcoating can comprise interpenetrating polymer networks (IPN). For thepurposes of the present invention, a definition of the IPN used by theInternational Union of Pure and Applied Chemistry (IUPAC) is adopted.The IUPAC describes the IPN as a polymer comprising two or more networkswhich are at least partially interlaced on a molecular scale, but notcovalently bonded to each other and cannot be separated unless chemicalbonds are broken. In other words, an IPN structure represents two ormore polymer networks that are physically entangled. One example of anIPN that can be used is a surface hydrogel.

One example of a product that can be used for forming the IPN is aPEG-based unsaturated product, for example, pre-polymer of PEG-acrylateor methacrylate having a general formula CH2=CX—COO—[CH2-CH2-O]n-H,where X is hydrogen (acrylates) or methyl (methacrylates). Weightaverage molecular weight of PEG-acrylate or methacrylate can be within arange of about 10,000 to 100,00 Daltons. PEG-acrylate prepolymer can beapplied on the surface of the drug-polymer or topcoat layer and cured,for example, using a radical initiator which is activated by UVradiation (UV initiators), light (light initiators), or heat (thermalinitiators). Examples of appropriate initiators include acetophenone,2,2-dimethoxy-2-phenol-acetophenone (UV initiators), camproquinone,ethyl-4-N,N,-dimethyl aminobenzoate (light initiators), and benzoylperoxide (thermal initiator). As a result of the curing process,PEG-acrylate will partially cross-link and partially physically entanglewith the polymer of the underlying layer thus forming the outermost coatlayer which includes an IPN. PEG-acrylate or methacrylate is intended tobroadly include poly(ethylene glycol)-diacrylate (PEG-diacrylate) andpoly(ethylene glycol)-dimethacrylate (PEG-dimethacrylate). PEG-acrylateor methacrylate and PEG-diacrylate or dimethacrylate can be optionallyterminated, for example, with stearic acid, to formPEG-acrylate-stearate PEG-methacrylate-stearate, respectively.

Examples of other products that can be used for forming the IPN includesuch unsaturated reactive products as N-vinylpyrrolidone, heparin andits derivatives, hyaluronic acid and its derivatives, somehydrogel-forming products such as poly(butyleneterephthalate-co ethyleneglycol) (PBT-PEG), and mixtures of any of these products with each otheror with PEG-acrylate or methacrylate.

Suitable derivatives of heparin include sodium heparin (Na-Hep), heparinbenzalkonium chloride (HBAC), and heparin tridodecyl methyl ammoniumchloride (HTDMAC). Derivatives of heparin can also include heparinmodified by introduction of photoactivatable groups in the heparinmolecule (the groups that are inactive under ambient conditions butbecome reactive when irradiated by UV-light, for example, at thefrequency of about 360 nm). Examples of photoactivatable groups includegroups derived from benzophenone or dithiocarbonate. Methods ofintroducing the photoactivatable groups into the molecules of heparinare known to those having ordinary skill in the art. Other derivativesof heparin can include heparin containing a moiety that tends to bind toalbumin, for example a the —(CH2)18- moiety.

Embodiments of the present invention can be further illustrated by thefollowing examples.

1. EXAMPLE 1

A first composition can be prepared by mixing the following components:

(a) between about 0.1 mass % and about 15 mass %, for example, about 2.0mass % of EVAL; and

(b) the balance of DMAC solvent.

The first composition can be applied onto a dealloyed porous layer, forexample, by spraying or dipping, to form the topcoat layer. The topcoatlayer can have, for example, a total solids weight of about 250 μg.

A second composition can be prepared by mixing the following components:

(c) between about 0.1 mass % and about 15 mass %, for example, about 2.0mass % of EVAL;

(d) between about 0.1 mass % and about 5 mass %, for example, about 1.0mass % of DURAFLO;

(e) between about 25 mass % and about 30 mass %, for example, 27.85 mass% of dimethylsulfoxide (DMSO) solvent;

(f) between about 5 mass % and about 6 mass %, for example, 5.65 mass %of tethrahydrofurane (THF) solvent; and

(g) the balance, DMAC solvent.

The second composition can be applied onto the dried topcoat layer, forexample, by spraying or dipping, to form the finishing coat layer havinga total solids weight of about 200 μg.

2. EXAMPLE 2

A first composition can be prepared by mixing the following components:

(a) between about 0.1 mass % and about 15 mass %, for example, about 2mass % of EVAL; and

(b) the balance, DMAC solvent.

The first composition can be applied onto the dealloyed porous layer,for example, by spraying, to form the topcoat layer having a totalsolids weight of about 300 μg.

A second composition can be prepared by mixing the following components:

(c) between about 0.1 mass % and about 15 mass %, for example, about 2.0mass % of EVAL;

(d) between about 0.1 mass % and about 5 mass %, for example, about 1.0mass % of poly(ethylene glycol) having molecular weight of about 5,000Daltons (PEG5000); and

(e) the balance, DMAC solvent.

The second composition can be applied onto the dried topcoat layer, forexample, by spraying or dipping, to form the finishing coat layer havinga total solids weight of about 200 μg.

3. EXAMPLE 3

A first composition can be prepared by mixing the following components:

(a) between about 0.1 mass % and about 15 mass %, for example, about 2mass % of EVAL; and

(b) the balance, DMAC solvent.

The first composition can be applied onto the dried drug-polymer layer,for example, by spraying, to form the topcoat layer having a totalsolids weight of about 300 μg.

A second composition can be prepared by mixing the following components:

(c) between about 0.1 mass % and about 15 mass %, for example, about 1.3mass % of EVAL;

(d) between about 0.1 mass % and about 5 mass %, for example, about 0.7mass % of PEG5000; and

(e) the balance, DMAC solvent.

The second composition can be applied onto the dried topcoat layer, forexample, by spraying or dipping, to form the finishing coat layer havinga total solids weight of about 200 μg.

4. EXAMPLE 4

A stent can be coated as described in Example 3, except the finishingcoat layer can have a total solids weight of about 150 μg.

5. EXAMPLE 5

A first composition can be prepared by mixing the following components:

(a) between about 0.1 mass % and about 15 mass %, for example, about 2mass % of EVAL; and

(b) the balance, DMAC solvent.

The first composition can be applied onto the dealloyed porous layer,for example, by spraying, to form the topcoat layer having a totalsolids weight of about 300 μg.

A second composition can be prepared by mixing the following components:

(c) between about 0.1 mass % and about 15 mass %, for example, about 1.3mass % of EVAL;

(d) between about 0.1 mass % and about 5 mass %, for example, about 0.7mass % of PEG5000; and

(e) the balance, DMAC solvent.

The second composition can be applied onto the dried topcoat layer, forexample, by spraying or dipping, to form the finishing coat layer havinga total solids weight of about 150 μg.

6. EXAMPLE 6

A first composition can be prepared by mixing the following components:

(a) between about 0.1 mass % and about 15 mass %, for example, about 2mass % of EVAL; and

(b) the balance, DMAC solvent.

The first composition can be applied onto the dealloyed porous layer,for example, by spraying, to form the topcoat layer having a totalsolids weight of about 250 μg.

A second composition can be prepared by mixing the following components:

(c) between about 0.1 mass % and about 15 mass %, for example, about 1.3mass % of EVAL;

(d) between about 0.1 mass % and about 5 mass %, for example, about 0.7mass % of PEG5000; and

(e) the balance, DMAC solvent.

The second composition can be applied onto the dried topcoat layer, forexample, by spraying or dipping, to form the finishing coat layer havinga total solids weight of about 150 μg.

7. EXAMPLE 7

A first composition can be prepared by mixing the following components:

(a) between about 0.1 mass % and about 15 mass %, for example, about 2mass % of EVAL; and

(b) the balance, DMAC solvent.

The first composition can be applied onto the dealloyed porous layer,for example, by spraying, to form the topcoat layer having a totalsolids weight of about 250 μg.

A second composition can be prepared by mixing the following components:

(c) between about 0.1 mass % and about 15 mass %, for example, about 1.3mass % of EVAL;

(d) between about 0.1 mass % and about 5 mass %, for example, about 0.7mass % of PEG5000; and

(e) the balance, DMAC solvent.

The second composition can be applied onto the dried topcoat layer, forexample, by spraying or dipping, to form the finishing coat layer havinga total solids weight of about 150 μg.

8. EXAMPLE 8

A first composition can be prepared by mixing the following components:

(a) between about 0.1 mass % and about 15 mass %, for example, about 2mass % of EVAL; and

(b) the balance, DMAC solvent.

The first composition can be applied onto the dealloyed porous layer,for example, by spraying, to form the topcoat layer having a totalsolids weight of about 200 μg.

A second composition can be prepared by mixing the following components:

(c) between about 0.1 mass % and about 15 mass %, for example, about 0.5mass % of EVAL;

(d) between about 0.1 mass % and about 5 mass %, for example, about 0.25mass % of hyaluronic acid; and

(e) the balance, DMSO solvent.

The second composition can be applied onto the dried topcoat layer, forexample, by centrifugation, to form the finishing coat layer having atotal solids weight of about 150 μg. The method of coating bycentrifugation is known to those having ordinary skill in the art.

9. EXAMPLE 9

A dealloyed porous layer can be coated as described in Example 8, exceptthe topcoat layer can have a total solids weight of about 100 μg.

10. EXAMPLE 10

A first composition can be prepared by mixing the following components:

(a) between about 0.1 mass % and about 15 mass %, for example, about 2mass % of EVAL; and

(b) the balance, DMAC solvent.

The first composition can be applied onto the dealloyed porous layer,for example, by spraying, to form the topcoat layer having a totalsolids weight of about 200 μg.

A second composition can be prepared by mixing the following components:

(c) between about 0.1 mass % and about 15 mass %, for example, about 0.5mass % of EVAL;

(d) between about 0.1 mass % and about 5 mass %, for example, about 0.25mass % of hyaluronic acid; and

(e) the balance, DMSO solvent.

The second composition can be applied onto the dried topcoat layer, forexample, by centrifugation, to form the finishing coat layer having atotal solids weight of about 150 μg.

11. EXAMPLE 11

A first composition can be prepared by mixing the following components:

(c) between about 0.1 mass % and about 15 mass %, for example, about 0.5mass % of silk elastin product;

(d) between about 0.1 mass % and about 5 mass %, for example, about 0.5mass % of hyaluronic acid; and

(e) the balance, distilled water.

The first composition can be applied onto the dealloyed porous layer,for example, by centrifugation, to form the finishing coat layer havinga total solids weight of about 150 μg.

12. EXAMPLE 12

A dealloyed porous layer can be coated as described in Example 11,except the topcoat layer can have a total solids weight of about 100 μg.

13. EXAMPLE 13

A first composition can be prepared by mixing the following components:

(a) between about 0.1 mass % and about 15 mass %, for example, about 2mass % of EVAL; and

(b) the balance, DMAC solvent.

The first composition can be applied onto the dried drug-polymer layer,for example, by spraying, to form the topcoat layer having a totalsolids weight of about 200 μg.

A second composition can be prepared by mixing the following components:

(c) between about 0.1 mass % and about 15 mass %, for example, about 0.5mass % of silk elastin product

(d) between about 0.1 mass % and about 5 mass %, for example, about 0.5mass % of hyaluronic acid; and

(e) the balance, distilled water.

The second composition can be applied onto the dried topcoat layer, forexample, by centrifugation, to form the finishing coat layer having atotal solids weight of about 150 μg.

14. EXAMPLE 14

A composition can be prepared, the composition including:

(a) about 3 mass % of PEG-acrylate having M, within a range of about10,000 and 100,000;

(b) about 1 mass % of 2,2-dimethoxy-2-phenol-acetophenone; and

(c) the balance a solvent mixture, the mixture containing de-ionizedwater and ethanol in a mass ratio of about 4:1.

The composition can be applied on the dealloyed porous layer andirradiated with UV-light at a wavelength of 360 nm for about 10 seconds,followed by drying, to form a topcoat layer comprising an IPN based onpoly(PEG-acrylate).

15. EXAMPLE 15

The dealloyed porous layer can be coated as described in Example 14,except that the same amount of benzoyl peroxide can be used the insteadof acetophenone. The topcoat layer-forming IPN can be formed bysubjecting the stent to a temperature of about 80° C. for about 5minutes.

16. EXAMPLE 16

A composition can be prepared, the composition including:

(a) about 20 mass % of N-vinylpyrrolidone;

(b) about 3 mass % of PEG-acrylate having Mw within a range of about10,000 and 100,000;

(c) about 1 mass % of 2,2-dimethoxy-2-phenol-acetophenone; and

(d) the balance of a solvent mixture, the mixture containing de-ionizedwater and ethanol in a mass ratio of about 4:1.

The composition can be applied on a dealloyed porous layer and a topcoatlayer comprising an IPN can be formed as described in Example 14.

17. EXAMPLE 17

A composition can be prepared, the composition including:

(a) about 3 mass % of PEG-acrylate having M, within a range of about10,000 and 100,000;

(b) about 3 mass % of heparin benzalkonium chloride (HBAC);

(c) about 1 mass % of acetophenone; and

(d) the balance a solvent mixture, the mixture containing iso-propanoland dimethylacetamide in a mass ratio of about 14:1.

The composition can be applied on a dealloyed porous layer and a topcoatlayer comprising an IPN can be formed as described in Example 14.

18. EXAMPLE 18

A composition can be prepared, the composition including:

(a) about 2 mass % of EVAL;

(b) about 0.7 mass % of PEG having M, of about 17,500 Daltons;

(c) about 0.7 mass % of PEG-diacrylate having M, of about 10,000Daltons;

(d) about 0.7 mass % of HBAC;

(e) about 0.1 mass % of 2,2-dimethoxy-2-phenol-acetophenone; and

(f) the balance dimethylacetamide solvent.

The composition can be applied on a dealloyed porous layer and a topcoatlayer comprising an IPN can be formed as described in Example 14.

19. EXAMPLE 19

A composition can be prepared, the composition including:

(a) about 7 mass % of EVAL;

(b) about 2 mass % of PEG having M, of about 17,500 Daltons;

(c) about 2 mass % of PEG-diacrylate having M, of about 10,000 Daltons;

(d) about 2 mass. % of HBAC;

(e) about 0.5 mass % of 2,2-dimethoxy-2-phenol-acetophenone; and

(f) the balance dimethylacetamide solvent.

The composition can be applied on a stent by spin coating and a topcoatlayer comprising an IPN can be formed.

20. EXAMPLE 20

A composition can be prepared, the composition including:

(a) about 2 mass % of EVAL;

(b) about 0.4 mass % of PEG having Mw of about 17,500 Daltons;

(c) about 0.2 mass % of HBAC; and

(d) the balance of dimethylacetamide solvent.

The composition can be applied on a dealloyed porous layer, for example,by spraying to form a topcoat layer.

21. EXAMPLE 21

A composition can be prepared, the composition including:

(a) about 3 mass % of EVAL;

(b) about 2 mass % of PEG having Mw of about 17,500 Daltons;

(c) about 2 mass % of sodium heparin (Na-Hep); and

(d) the balance, a solvent blend, the blend comprising formamide (FA),methanol (MeOH) and dimethylacetamide (DMAC) in a mass ratioFA:MeOH:DMAC of about 1:1.05:3.

To prepare the composition, Na-Hep can be dissolved in FA first at atemperature between about 60° C. and 100° C., to form about 10%Na-Hep/FA solution, followed by adding EVAL, PEG, MeOH and DMAC to theNa-Hep/FA solution.

The composition can be applied on a dealloyed porous layer, for example,by spraying while the temperature of the composition is maintainedbetween about 55° C. and 70° C. to form a topcoat layer.

The process of the release of the drug from a coating having bothtopcoat and finishing coat layers includes at least three distinctivesteps. First, the drug is absorbed by the polymer of the topcoat layeron the dealloyed porous layer/topcoat layer interface. Next, the drugdiffuses through the topcoat layer using empty spaces between themacromolecules of the topcoat layer polymer as pathways for migration.Next, the drug arrives to the topcoat layer/finishing layer interface.Finally, the drug diffuses through the finishing coat layer in a similarfashion, arrives to the outer surface of the finishing coat layer, anddesorbs from the outer surface. At this point, the drug is released intothe blood stream or adjacent tissue. Consequently, a combination of thetopcoat and finishing coat layers, if used, can serve as a rate limitingbarrier.

As mentioned previously, the topcoat or surface coating itself may alsocontain one or more therapeutic agents that are the same or differentfrom the therapeutic agents contained in the dealloyed porous zone. Theappropriate mixture of polymers may be coordinated with biologicallyactive materials contained in the porous zone and/or the topcoat layerto produce desired effects when coated on a medical device in accordancewith the invention. The biologically active agents of the topcoat, ifany, may be incorporated by diffusion of the agents from the dealloyedpolymer layer. If the drugs are suspended in the solution, they shouldbe dispersed as fine particles ranging from about 1 to about 100 micronsin average particle size. Alternatively, if a polymer having arelatively low melting point is used, the polymer and biologicallyactive agent can be blended in the molten stage (such as by casting orcoextrusion) if the biologically active agent does not degrade at themolten temperature. In one embodiment, the ratio of topcoat thickness toaverage particle diameter is preferably greater than about 3, and morepreferably greater than about 5.

The concentration or loading of the biologically active material in thetopcoat layer may be varied according to the therapeutic effectsdesired. Also, the loading, if any, in terms of the ratio of therapeuticagent to polymer in the topcoat layer, will depend upon the efficacy ofthe polymer in securing the therapeutic agent onto the medical deviceand the rate at which the coating is to release the therapeutic agent tothe body tissue. Generally, when used with a therapeutic agent, thetopcoat layer may contain about 0.1 to about 90% by weight or preferablyabout 10 to about 45% by weight of the biologically active material.Most preferably, about 25% to about 40% by weight of the drug should beincorporated in the dealloyed layer.

The topcoat layer composition generally may be prepared by addingmicronized drug particles into a selected amount of polymer. Solvent andoptional crosslinking agents are then added to this mixture which isthen stirred until it is homogeneous. Depending on the nature of thebiologically active material and the solvent and polymers used, themixture need not be a solution. The drug particles need not be dissolvedinto the mixture but may be suspended therein.

In one embodiment, the topcoat layer will generally be prepared to besubstantially free of any ionic surfactant. However, small amounts maybecome present, especially at an interface between a topcoat layer and aporous zone. For instance, small amounts of ionic surfactant may becomepresent as a result of penetration during a topcoat layer sprayingprocess or due to migration from the topcoat layer during shelf storage.The porous zone, apart from the interface with the topcoat layer, willpreferably have less than about 0.5 weight percent complex, morepreferably less than about 0.4 weight percent complex.

Solvents suitable for forming the topcoat layer composition are oneswhich can dissolve the polymer into solution and do not alter oradversely impact the therapeutic properties of the biologically activematerial contained in the either the porous zone or topcoat layer.Examples of useful solvents for silicone include tetrahydrofuran (THF),chloroform and dichloromethane.

To enhance the stability of the topcoat layer and the timed or long-termrelease of the therapeutic agents, crosslinkers may be incorporated intothe topcoat layer. For example, hydridosilane may be used as acrosslinking agent for silicone.

Once prepared, the topcoat mixture is then applied to a porous zone orthe surface of the medical device. The topcoat layer composition may beapplied by dipping the medical device into the composition or byspraying the composition onto at least a portion of the device. Thethickness of the topcoat layer formed may range from about 1 micron toabout 100 microns and preferably from about 2 microns to about 15microns.

Since different topcoat thicknesses can be readily achieved by adjustingthe number of spray cycles, spray coating the medical device ispreferred. In one embodiment, an airbrush such as a Badger Model 150(supplied with a source of pressurized air) may be used to coat thedevice. If a significant amount of surface area is to be coated, it maybe preferable to place the device in a rotating fixture to facilitatethe coverage of the device's surface. For example, to coat the entiresurface of a vascular stent, the ends of the device are fastened to arotating fixture by resilient retainers, such as alligator clips. Thestent is rotated in a substantially horizontal plane around its axis.The spray nozzle of the airbrush may be placed 2-4 inches from thedevice.

The thickness of the topcoat can be adjusted by the speed of rotationand the flow rate of the spray nozzle. The speed of rotation is usuallyadjusted at about 30 to about 50 rpm, typically at about 40 rpm. Theflow rate of the spray nozzle, which can range from about 4 to about 10ml coating per minute may also be adjusted. Usually, a number ofspraycoats will be required to achieve the desired thickness of atopcoat layer. If a non-spray process is utilized, such as dip coating,casting or coextrusion, then one coat may be sufficient.

Moreover, several topcoat layers of different compositions may be usedto further modify the release kinetics from the porous zone, or so thatmore than one drug and/or polymer may be incorporated into the topcoat.The placement or order of the different layers may also be determined bythe diffusion or elution rates of the therapeutic agent involved, thedesired rate of delivering the therapeutic agent to the body tissue, aswell as the degradation characteristics of the polymer or therapeuticagent.

After application of the topcoat layer, the polymer can be cured toproduce a polymer matrix, with the biologically active material asdesired in some embodiments, and the solvent evaporated. Certainpolymers, such as silicone, can be cured at relatively low temperatures,(e.g. room temperature) in what is known as a room temperaturevulcanization (RTV) process. More typically, the curing/evaporationprocess involves higher temperatures so that the coated device is heatedin an oven. Typically, the heating occurs at approximately 90 degreesCelsius or higher for approximately about 1 to about 16 hours whensilicone is used. For certain coatings where the polymer used or thetherapeutic agent within the topcoat, if any, such as ones containingdexamethasone, can tolerate greater temperatures, the heating may occurat temperatures as high as about 150 Celsius. The time and temperatureof heating will of course vary with the particular polymer, drugs,solvents and/or crosslinkers used. One of skill in the art is aware ofthe necessary adjustments to these parameters. Also, the devices may becured after the topcoat layer has been applied.

In one embodiment, the topcoat layer contains an ionic surfactant-drugcomplex that is preferably prepared by dissolving the complex in asolvent or a mixture of solvents, However, it can also be prepared byblending the ionic surfactant drug complex with polymer(s) orpolymer(s)/solvent mixtures. Suitable drugs have been described above.Appropriate ionic surfactants include quaternary ammonium compounds suchas one of the following: benzalkonium chloride, tridodecylmethylammoniumchloride (TDMAC), cetylpyridinium chloride,benzyldimethylstearylammonium chloride, benzylcetyl dimethyl ammoniumchloride. An additional example of an appropriate ionic surfactantincludes a polymeric surfactant, such as a quaternary ammonium salt ofacrylate polymer including 2-(trimethyl amine)-ethyl methacrylatebromide, or a quaternary ammonium salt of cellulose such as JR400 andQUATRISOFT manufactured by Union Carbide. Preferably, the ionicsurfactant comprises TDMA.

The surfactant-drug complex can either be purchased on the open marketor made in the laboratory. For instance, benzalkonium chloride is madeand sold by ALDRICH. TDMA-heparin is made and sold by STS POLYMERS. Theskilled artisan is aware of methods for making surfactant-drugcomplexes.

The concentration or loading of biologically active material in theouter layer, if any, may be varied according to the therapeutic effectsdesired. Generally, the topcoat layer may contain about 0 to about 100%by weight or sometimes about 30 to about 100% by weight of the complexof the biologically active material. In some embodiments, about 45 toabout 100% by weight of the drug complex should be incorporated in thetopcoat layer.

The topcoat layer composition is then applied to the medical device. Thecomposition can be applied by such methods as dipping, casting,extruding or spray coating to form a layer in which some of thedrug-surfactant complex will penetrate into the very top of porestructure of the porous zone. Typically, spray coating the topcoat layeronto the medical device is preferred since it permits the thickness ofthe coating to be readily adjusted. The thickness of the topcoat layercan range from about 0.1 to about 10 microns. Preferably, this layer isabout 1 to about 5 microns thick. When spray coating, 1-2 spray cyclesare preferred, however additional cycles may be applied depending uponthe coating thickness desired.

The coating thickness ratio of the outer layer to the dealloyed layermay vary from about 1:2 to 1:100 and is preferably in the range of fromabout 1:10 to 1:25.

The release rate and release profile of the therapeutic agent(s) fromthe porous zone and/or topcoat layer may be affected by the thickness ofthe topcoat layer as well as the concentration of any ionically boundtherapeutic in that layer. If a greater amount of the biologicallyactive material is to be delivered initially, thinner topcoat layers maybe used.

To prepare the stabilized surface coatings of this invention, themedical devices may be exposed to a low energy, relativelynon-penetrating energy source such as gas plasma, electron beam energy,or corona discharge after they are covered with at least a layer ofsurface coating. The gas used in the gas plasma treatment can bepreferably argon or other gases such as nitrogen, helium or hydrogen.Preferably the coated device is first heat cured at about 40° Celsius toabout 150° Celsius prior to the exposure to the energy source for about30 seconds to about 30 minutes. Relatively penetrating energy sourcessuch as gamma radiation are typically but not always avoided.

Also, such treatment can be applied to the device prior to completingthe application of the surface coating. For example, after the device isdealloyed to form the porous zone it can be heated and exposed to thelow energy, relatively non-penetrating energy source. The treatment canbe repeated after other layers have been applied.

In one suitable method, the medical devices are placed in a chamber of aplasma surface treatment system such as a Plasma Science 350(Himont/Plasma Science, Foster City, Calif.). The system is equippedwith a reactor chamber and RF solid-state generator operating at about13.56 mHz and from about 0 to about 500 watts power output and beingequipped with a microprocessor controlled system and a complete vacuumpump package. The reaction chamber contains an unimpeded work volume ofabout 16.75 inches (42.55 cm) by 13.5 inches (34.3 cm) by about 17.5inches (44.45 cm) in depth.

In the plasma process, coated medical devices are placed in a reactorchamber and the system is purged with nitrogen and a vacuum applied toabout 20 to about 50 mTorr. Thereafter, inert gas (argon, helium ormixture of them) is admitted to the reaction chamber for the plasmatreatment. A highly preferred method of operation consists of usingargon gas, operating at a power range from about 200 to about 400 watts,a flow rate of about 150to about 650 standard ml per minute, which isequivalent to about 100 to about 450 mTorr, and an exposure time fromabout 30 seconds to about 5 minutes. The devices can be removedimmediately after the plasma treatment or remain in the argon atmospherefor an additional period of time, typically five minutes.

Moreover, after the medical devices are coated, they are typicallysterilized. Methods of sterilization are known in the art. For example,the devices can be sterilized by exposure to gamma radiation at about2.5 to about 3.5 Mrad or by exposure to ethylene oxide. Forsterilization, exposure to gamma radiation is a preferred method,particularly for heparin containing coatings. However, for certainmedical devices which undergo mechanical challenges, such as expandablevascular stents, it has been found that subjecting such coated devicesto gamma radiation sterilization may reduce their ability to expand. Toavoid such reduction, the gas plasma treatment described above should beapplied to the coated devices as a pretreatment for gamma sterilization.

Although the present invention has been described in relation to variousexemplary embodiments, various additional embodiments and alterations tothe described embodiments are contemplated within the scope of theinvention. Thus, no part of the foregoing description should beinterpreted to limit the scope of the invention as set forth in thefollowing claims. For all of the embodiments described above, the stepsof the methods need not be performed sequentially.

1. A stent for insertion into a body structure, comprising: a tubularmember having: a first end and a second end, a lumen extending along alongitudinal axis between the first end and the second end, an ablumenalsurface, a lumenal surface; and at least one porous layer, the porouslayer comprising an interstitial structure and an interstitial space;wherein the interstitial space is generally configured by the removal ofat least a portion of at least one sacrificial material by a thermaldealloying process from a mixture comprising at least one sacrificialmaterial with one or more structural materials that comprise theinterstitial structure of the porous layer; and wherein the porous layeris adapted to receive and release at least one therapeutic agent.
 2. Thestent for insertion into a body structure as in claim 1, wherein atleast one sacrificial material is selected for its boiling point.
 3. Thestent for insertion into a body structure as in claim 1, wherein atleast one sacrificial material is selected for its vapor pressure. 4.The stent for insertion into a body structure as in claim 1, wherein thethermal dealloying process comprises the application of a heat source.5. The stent for insertion into a body structure as in claim 4, whereinthe heat source is a light source.
 6. The stent for insertion into abody structure as in claim 5, wherein the light source is a laser. 7.The stent for insertion into a body structure as in claim 5, wherein thelight source is an infrared light source.
 8. The stent for insertioninto a body structure as in claim 5, wherein the light source is anultraviolet light source.
 9. The stent for insertion into a bodystructure as in claim 4, wherein the heat source is an inductive heatsource.
 10. The stent for insertion into a body structure as in claim 4,wherein the heat source is an ultrasound source.
 11. The stent forinsertion into a body structure as in claim 1, wherein at least onesacrificial material comprises a form of magnesium.
 12. The stent forinsertion into a body structure as in claim 4, wherein the applicationof a heat source is performed in a vacuum of about 10⁻⁵ torr or less.13. The stent for insertion into a body structure as in claim 12,wherein the application of a heat source is performed in a vacuum ofabout 10⁻⁶ torr or less.
 14. The stent for insertion into a bodystructure as in claim 13, wherein the application of a heat source isperformed in a vacuum of about 10⁻⁹ torr or less.
 15. The stent forinsertion into a body structure as in claim 4, wherein the heat sourceis capable of heating a portion of the mixture in a temperature of atleast about 400° Celsius.
 16. The stent for insertion into a bodystructure as in claim 15, wherein the heat source is capable of heatinga portion of the mixture in a temperature of at least about 500°Celsius.
 17. The stent for insertion into a body structure as in claim16, wherein the heat source is capable of heating a portion of themixture in a temperature of at least about 600° Celsius.
 18. The stentfor insertion into a body structure as in claim 1, wherein the pores ofthe porous layer are modified by the application of an etchant to theporous layer.
 19. The stent for insertion into a body structure as inclaim 18, wherein the etchant has anisotropic properties.
 20. The stentfor insertion into a body structure as in claim 18, wherein the etchanthas isotropic properties.
 21. A therapy-eluting medical device,comprising: at least one component of a medical device having at leastone therapy-eluting surface comprising an interstitial structure and aninterstitial space, wherein the interstitial space is configuredgenerally by the removal of at least a portion of one sacrificialmaterial by a thermal dealloying process from a mixture comprising atleast one sacrificial material and one or more structural materials thatcomprise the interstitial structure of the porous layer; and wherein thetherapy-eluting surface is adapted to receive and release at least onetherapeutic agent.
 22. A method for manufacturing a medical device withat least one non-polymeric porous layer, comprising the steps of:providing at least a component of a medical device having at least onesurface; depositing a layer of a material onto at least a portion of thesurface; the layer of material comprising at least one sacrificialcomponent and at least one structural component and at least onecomponent is not a polymer or therapeutic agent; and thermally removingat least a portion of at least one sacrificial component to form aninterstitial space.
 23. The method for manufacturing a medical devicewith at least one non-polymeric porous layer as in claim 22, furthercomprising increasing the interstitial space with an etchant.
 24. Themethod for manufacturing a medical device with at least onenon-polymeric porous layer as in claim 23, wherein the etchant hasisotropic properties.
 25. The method for manufacturing a medical devicewith at least one non-polymeric porous layer as in claim 23, wherein theetchant has anisotropic properties.
 26. The method for manufacturing amedical device with at least one non-polymeric porous layer as in claim22, wherein the thermally removing step is performed in a vacuum. 27.The method for manufacturing a medical device with at least onenon-polymeric porous layer as in claim 22, wherein the thermallyremoving step is performed using a laser.